AU4701799A - Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions - Google Patents

Description

WO 00/04892 PCT/US99/13948 -1 COADMINISTRATION OF ACAT AND MMP INHIBITORS FOR THE TREATMENT OF ATHEROSCLEROTIC LESIONS BACKGROUND OF THE INVENTION Enzymes known as native matrix metalloproteinases (MMP) are classes of 5 naturally occurring enzymes found in most mammals. They are zinc proteases that hydrolyze collagens, proteoglycans, and glycoproteins. The classes include gelatinase A and B, stromelysin-l and -2, fibroblast collagenase, neutrophil collagenase, matrilysin, metalloelastase, and interstitial collagenase. These enzymes are implicated in a number of diseases which result from breakdown of 10 connective tissues, such as rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, and even tumor metastasis. The expression of MMPs in atherosclerosis is discussed in White A., Bocan T.M.A., Boxer P.A., Peterson J.T., Schrier D. Emerging therapeutic advances for the development of second generation matrix metalloproteinase inhibitors. Curr. Pharm. Design 15 3:45-58 (1997). To date, inhibitors of matrix metalloproteinases have not been utilized with ACAT inhibitors. United States Patent Application 08/987167 filed December 8, 1997, teaches MMP inhibitors and their preparation and is hereby incorporated by reference. 20 Compounds which inhibit acyl-coenzyme A:cholesterol acyltransferase are known as ACAT inhibitors. Certain ACAT inhibitors and the methods for preparing them are taught in United States Patent 5,491,172 and its divisional 5,633,287 which are hereby incorporated by reference. United States Patent 5,756,545 covers MMP inhibitors especially 25 2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid. This patent is hereby incorporated by reference. United States Patent 5,441,975 teaches ACAT inhibitors, especially

N-(

2

,

6 -Diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide. This and other patents in the same patent family: 5,646,170; 5,693,657; and 30 5,366,987 are hereby incorporated by reference.

WO 00/04892 PCT/US99/13948 -2 SUMMARY OF THE INVENTION The instant invention is the coadministration of ACAT and MMP inhibitors for the reduction of both macrophage and smooth muscle cell components of atherosclerotic lesions in a mammal, particularly a human. The 5 lesions are directly reduced, and so, the expansion of existing lesions and the development of new ones is impaired. Certain ACAT inhibitors and certain MMP inhibitors are disclosed as suitable for coadministration. Pharmaceutical compositions of the inhibitors are also included in the 10 invention. DETAILED DESCRIPTION OF THE INVENTION Coadministration of a bioavailable ACAT inhibitor with a matrix metalloproteinase (MMP) inhibitor can blunt the development of atherosclerotic lesions and promote development of a stable plaque morphology. ACAT 15 inhibitors have been shown to reduce the accumulation of monocyte-macrophages within atherosclerotic lesions of rabbits. In addition, monocyte-macrophages have been reported to secrete such matrix metalloproteinases as MMP-7 and -9 while smooth muscle cells are noted to secrete MMP- 1, -2, and -3. Inhibition of ACAT while directly reducing the accumulation of lipid-filled monocyte-macrophages 20 will decrease the source of MMPs. Inhibition of MMPs will also limit the development of atherosclerotic lesions through reducing smooth muscle cell and monocyte migration into the development intima by limiting extracellular matrix remodeling. Coadministration of both agents will limit the development of new lesions by inhibiting cellular accumulation and stabilize the developed lesions by 25 preventing both matrix remodeling and reducing the number of lipid-filled monocyte-macrophages, a source of MMP-7 and -9. The instant invention is a method for treating and/or preventing atherosclerotic lesions comprising coadministrating one or more MMP inhibitors and one or more ACAT inhibitors.

WO 00/04892 PCTIUS99/13948 -3 The invention is further a method for preventing plaque rupture and for promoting lesion regression by administering a combination of an ACAT inhibitor and an MMP inhibitor. The method is practiced by administering a chemical compound effective 5 in inhibiting the biological activity of a matrix metalloproteinase such as collagenase, stromelysin, gelatinase, or elastase. The numerous compounds known to be matrix metalloproteinase inhibitors are useful in the practice of this invention. The method is practiced by administering a chemical compound which 10 inhibits the enzyme acyl-coenzyme A:cholesterol acyltransferase. The numerous compounds known as ACAT inhibitors are useful in the practice of this invention. A "matrix metalloproteinase inhibitor" as used herein is any chemical compound that inhibits by at least five percent the hydrolytic activity of at least one matrix metalloproteinase enzyme that is naturally occurring in a mammal. 15 Such compounds are also referred to as "MMP inhibitors." Numerous matrix metalloproteinase inhibitors are known, and all are useful in the method of this invention. For example, 4-biarylbutyric and 5-biarylpentanoic acid derivatives are described in United States Patent Application 339846 filed November 15, 1994, which is incorporated herein by reference. The compounds are defined generally 20 as (T)xA-B-D-E-G. Over 400 specific compounds are named, and each is incorporated herein and can be employed in this invention. Especially preferred compounds to be utilized include the following: [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-a-(2-methylpropyl)-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-, 25 (S)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-, (R)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro--(2-methylpropyl)-y-oxo-, (S); [1,1 '-Biphenyl]-4-butanoic acid, 4 '-chloro-p-(2-methylpropyl)-y-oxo-, 30 (R)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-bromo-y-oxo-; WO 00/04892 PCTIUS99/13948 -4 [1,1'-Biphenyl]-4-butanoic acid, 4'-fluoro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 2'-fluoro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 2'-chloro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 2',4'-difluoro-y-oxo-; 5 [1,1'-Biphenyl]-4-butanoic acid, 3'-chloro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, a-(2-methyl-propyl)-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-bromo-a-(2-methylpropyl)-y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-fluoro-a-(2-methylpropyl)-y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-ethyl-a-(2-methylpropyl)-y-oxo-; 10 [1,1'-Biphenyl]-4-butanoic acid, 2 '-fluoro-u-(2-methylpropyl)-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 2 '-chloro-a-(2-methylpropyl)-y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-methoxy-x-(2-methylpropyl)-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 2

',

4 '-difluoro-ax-(2-methylpropyl)-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-methyl-a-(2-methylpropyl)-y-oxo-; 15 [1,1'-Biphenyl]-4-butanoic acid, a-( 2 -methyl-propyl)-y-oxo-4'-pentyl-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-ax-methylene-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 2 '-chloro-x-methylene-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a.-methyl-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-a-pentyl-; 20 Benzenebutanoic acid, 4 -chloro-a-(2-methylpropyl)-y-oxo-; Benzenebutanoic acid, 4 -methyl-a.-methylene-y-oxo-; 2-Butenoic acid, 4-(4'-chloro[1,1'-biphenyl]-4-yl)-4-oxo-, (E)-; 2-Butenoic acid, 4-[4-(4-chlorophenyoxy)-phenyl]-4-oxo, (E)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-hydroxy-ax-(2-methylpropyl)-y-oxo-; 25 [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-p-methylene-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-hydroxy-c-(2-methylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-hydroxy-a-(2-methylpropyl)-; 2(3H)-Furanone, 5-(4'-chloro[1,1'-biphenyl]-4-yl)dihydro-3 (2-methylpropyl)-; 30 2(3H)-Furanone, 5-(4'-chloro[1,1'-biphenyl]-4-yl)dihydro-3-(2 methylpropyl)-; WO 00/04892 PCT/US99/13948 -5 [1,1'-Biphenyl]-4-butanoic acid, 3

',

4 '-dichloro-y-oxo-a-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 3',5'-dichloro-y-oxo-(-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-(acetyloxy)-y-oxo-X-(3 phenylpropyl)-; 5 Benzenepentanoic acid, a-[ 2

-[

4 -(5-chloro-2-thienyl)phenyl]-2-oxoethyl]-; 2-Furancarboxylic acid, 5-[4-(3-carboxy-1-oxo-6-phenylhexyl)phenyl]-; Benzenepentanoic acid, u- [2-oxo-2- [4-(3 -pyridinyl)phenyl] ethyl]-; Benzenepentanoic acid, a-[ 2 -oxo- 2

-[

4 -[6-(pentyloxy)-3-pyridinyl] phenyl] ethyl]-; 10 [1,1 '-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentylthio)-a-(3 phenylpropyl) ; [1,1'-Biphenyl]-4-butanoic acid, 4 '-methoxy-y-oxo-a-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 3'-chloro-4'-fluoro-y-oxo-aL-(3 phenylpropyl)-; 15 [1,1'-Biphenyl]-4-butanoic acid, 4 '-ethoxy-y-oxo-a.-(3-phenylpropyl)-; Benzenepentanoic acid, ax- [2-oxo-2- [4-(3 -thienyl)phenyl]ethyl]-; [1,1'-Biphenyl]-4-butanoic acid, 2

',

4 '-dichloro-y-oxo-a-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-formyl-y-oxo-x-(3-phenylpropyl)-; [1,1 '-Biphenyl]-4-butanoic acid, y-oxo-a-(3-phenylpropyl)-3',5' 20 bis(trifluoromethyl)-; Benzenepentanoic acid, a-[2-oxo-2- [4-(2-thienyl)phenyl] ethyl]-; [1,1'-Biphenyl]-4-butanoic acid, 7-oxo-x-(3-phenylpropyl)-3' (trifluoromethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 2 '-formyl-y-oxo-a-(3-phenylpropyl)-; 25 [1,1'-Biphenyl]-4-butanoic acid, 4-hydroxy-y-oxo-a-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 7-oxo-a-(3-phenylpropyl)-4'-propoxy-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo- 4 '-(pentyloxy)-aL-(3 phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentyloxy)-a.-(3 30 phenylpropyl)-, (S)-; WO 00/04892 PCT/US99/13948 -6 [1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentyloxy)-a-(3 phenylpropyl)-, (R)-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-(hexyloxy)-y-oxo-X-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-butoxy-y-oxo-a-(3-phenylpropyl)-; 5 [1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(3-phenylpropoxy)-X (3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-(I-methylethoxy)-y-oxo-c (3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-(heptyloxy)-y-oxo-aX 10 (3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-(cyclohexyl-methoxy)-y-oxo-a (3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-(2-methyl-propoxy)-y-oxo-a (3-phenylpropyl)-; 15 [1,1 '-Biphenyl]-4-butanoic acid, y-oxo-ax-(3-phenylpropyl)-4' (2-propenyloxy)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-heptyl-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-ax-decyl-y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-nitro-y-oxo-a-(2-phenylethyl)-; 20 [1,1'-Biphenyl]-4-butanoic acid, 4 '-cyano-y-oxo-a-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-ax-[2-(2-iodophenyl)ethyl] y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-chloro-c-[2-(3-iodophenyl)ethyl] y-oxo-; 25 [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-ax-[2-(4-iodophenyl)ethyl] y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-ax-[2-(3,5 dimethoxyphenyl)ethyl]-y-oxo-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-c-phenyl-; 30 [1,1 '-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-a-(phenylmethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-a-(2-phenylethyl)-; WO 00/04892 PCT/US99/13948 -7 [1,1 '-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-a-[(trimethylsilyl) methyl]-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-bromo-y-oxo-a-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, -y-oxo-a-(3-phenylpropyl)-; 5 [1,1 '-Biphenyl]-4-butanoic acid, 4 '-amino-y-oxo-ca-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-x-(2-phenylethyl)-4' [[(phenylmethoxy)carbonyl]amino]-; [1,1'-Biphenyl]-4-butanoic acid, 4'-[[(1,1-dimethylethoxy) carbonyl] amino] -y-oxo-ax-(2-phenylethyl)-; 10 [1,1 '-Biphenyl]-4-butanoic acid, 4'-(acetylamino) y-oxo-a (2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, y-oxo-4'-[(1 -oxopentyl)amino]-a (2-phenylethyl)-; [1,1*'-Biphenyl]-4-butanoic acid, 4'-[(3,3-dimethyl-1-oxobutyl)amino] 15 y-oxo-a.-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-a-[2-[2-(methoxycarbonyl) phenyl] ethyl] -y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, ax-[ 2

-(

2 -carboxyphenyl)ethyl]-4'-chloro 'y-oxo-; 20 [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-a-[2-[2-[(diethylamino) carbonyl]phenyl]ethyl]-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3 [(diethylamino)carbonyl]phenyl] ethyl] -y-oxo-, (S)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-ax-[2-[3 25 [(diethylamino)carbonyl]phenyl]ethyl]-y-oxo-, (R)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[(phenylmethoxy)methyl]-, (1au,2p,5$)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-(phenoxymethyl)-, (1 c,2p,5p)-; 30 Cyclopentanecarboxylic acid, 2 -[(benzoyloxy)-methyl]-5-[(4'-chloro[1,1' biphenyl]-4-yl)carbonyl]-, (1 ,2f,5$)-; WO 00/04892 PCT/US99/13948 -8 1,2-Benzenedicarboxylic acid, 1-[[2-carboxy-3-[(4'-chloro[ 1,1 '-biphenyl] 4-yl)carbonyl]cyclopentyl]-methyl]-2-methyl ester,( 1X,2 ,3aC)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[(2-thienylthio)methyl]-, (la,2p,5p)-; 5 Cyclopentanecarboxylic acid, 2-[(benzoylamino)methyl]-5-[(4' chloro[l,1'-biphenyl]-4-yl)carbonyl]-, ( x,2p,5p)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[[(2-methoxyethoxy)methoxy]methyl]-, (lx,2$,5 )-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1 '-biphenyl]-4-yl)carbonyl] 10 5-[[(phenylmethyl)thio]methyl]-, (1ac,2p,5 )-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[(phenylthio)methyl]-, (1 x,2$,5$)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[(propylthio)methyl]-, (1 c,2$,5p)-; 15 Cyclopentanecarboxylic acid, 2-[(2-benzothiazolylthio)methyl]-5-[(4' chloro[1,1'-biphenyl]-4-yl)carbonyl]-, (1x,2p,5p)-; Benzoic acid, 2-[[[2-carboxy-3-[(4'-chloro[ 1,1 '-biphenyl] 4-yl)carbonyl]cyclopentyl]methyl]thio]-, 1-methyl ester, (l a,2p,3x)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 20 5-[[[(phenylmethoxy)carbonyl] -amino]methyl]-, (1 c,26,5 )-; Benzoic acid, 2-methyl-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl] 4-yl)carbonyl]cyclopentyl]methyl ester, (1 a,2p,3cx)-; Benzoic acid, 3-methyl-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl] 4-yl)carbonyl]cyclopentyl]methyl ester, (1 x,2p,3cx)-; 25 Benzoic acid, 4-methyl-, [2-carboxy-3-[(4'-chloro[ 1,1 '-biphenyl] 4-yl)carbonyl]cyclopentyl]methyl ester, (1a,2p,3x)-; Benzoic acid, 2-methoxy-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl] 4-yl)carbonyl]cyclopentyl]methyl ester, (a,2 1,3a)-; Benzoic acid, 3-methoxy-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl] 30 4-yl)carbonyl]cyclopentyl]methyl ester, (1a,2 ,3uc)-; WO 00/04892 PCT/US99/13948 -9 Benzoic acid, 4-methoxy-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl] 4-yl)carbonyl]cyclopentyl]methyl ester, (1la,2p,3 a)-; Cyclopentanecarboxylic acid, 2 -[(2-benzoxazolylthio)methyl]-5-[(4' chloro[1,1'-biphenyl]-4-yl)carbonyl]-, (1c,2p,5p)-; 5 Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[(1,3-dihydro-4-nitro-1,3-dioxo-2H-isoindol-2-yl)methyl]-, (1 a,2p,5p)-; Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5- [(1,3 -dihydro-5-nitro- 1,3-dioxo-2H-isoindol-2-yl)methyl] -, (1al,2p,5 )-; 2H-Benz[f~isoindole-2-butanoic acid, a-[2-(4'-ethoxy[1,1'-biphenyl]-4-yl) 10 2-oxoethyl]-1,3-dihydro-1,3-dioxo-; [1,1'-Biphenyl]-4-butanoic acid, a-(acetylamino)-4'-chloro-y-oxo-; 2H-Isoindole-2-hexanoic acid, a-[2-(4'-chloro[1,1'-biphenyl]-4-yl) 2-oxoethyl]-1,3-dihydro-1,3-dioxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-(methoxycarbonyl) 15 phenyl]thio]methyl]-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-x-[[(2,6-(dimethylphenyl) thio]methyl]-,y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[4-fluoro 2 -(methoxycarbonyl)phenyl]thio]methyl]-y-oxo-; 20 [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-[(diethylamino) carbonyl]phenyl]thio]methyl]-7-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[2-[(dimethylamino) carbonyl]phenyl]thio]methyl]-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-[(dimethylamino) 25 carbonyl]phenyl]thio]methyl-]-y-oxo-; Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, 3

-[[

4 '-(pentyloxy)[1,1' biphenyl]-4-yl]carbonyl]-, (2-endo,3-exo)-; 1-Cyclopentene-1-carboxylic acid, 5-[(4'-chloro[ 1,1 '-biphenyl] 4-yl)carbonyl]-; 30 Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 5-[(phenylmethyl)thio]-, (1 a,2p,5 a)-; WO 00/04892 PCT/US99/13948 -10 Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl-4-yl)carbonyl] 5-[(phenylmethyl)thio]-, (1la,2p,5 )-; I-Cyclopentene-1-carboxylic acid, 5-[[ 4 '-(pentyloxy)[1,1'-biphenyl] 4-yl]carbonyl]-; 5 I-Cyclopentene-1-carboxylic acid, 5-[[4'-(hexyloxy)[1,1'-biphenyl] 4-yl)]carbonyl]-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-hydroxy-y-oxo-a-[(phenylthio) methyl]-; [1,1'-Biphenyl]-4-butanoic acid, ax-[2-[2-[(butylamino) 10 carbonyl]phenyl] ethyl]-4'-chloro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, a-[ 2 -(3-carboxyphenyl)ethyl]-4'-chloro y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-ax-[2-[3-[(diethylamino) carbonyl]phenyl]ethyl]-y-oxo-; 15 [1,1'-Biphenyl]-4-butanoic acid, a-[ 2 -[3-[(butylamino)carbonyl] phenyl] ethyl]-4'-chloro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-x-[2-[4-[(diethylamino) carbonyl]phenyl]ethyl]-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, c-[2-[4-[(butylamino) 20 carbonyl]phenyl]ethyl]-4'-chloro-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, -[ 2 -(4-carboxyphenyl)ethyl]-4'-chloro y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-methoxy--y-oxo-a-(2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4 '-hydroxy-y-oxo-x-(2-phenylethyl)-; 25 [1,1'-Biphenyl]-4-butanoic acid, 4 '-ethoxy-y-oxo-ax-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-a-( 2 -phenylethyl)-4'-propoxy-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentyloxy)-a-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-(hexyloxy)-y-oxo-a-(2-phenylethyl)-; [1,1 '-Biphenyl]-4-butanoic acid, 4'-butoxy-y-oxo-a-(2-phenylethyl)-; 30 [1,1'-Biphenyl]-4-butanoic acid, y-oxo-a-(2-phenylethyl)-4' (phenylmethoxy)-; WO 00/04892 PCTIUS99/13948 -11 [1,1'-Biphenyl]-4-butanoic acid, a-[ 2 -(3-iodophenyl)ethyl]-y-oxo-4' (pentyloxy)-; [1,1'-Biphenyl]-4-butanoic acid, a-[2-(3-iodophenyl)ethyl]-y-oxo-4' (phenylmethoxy)-; 5 [1,1'-Biphenyl]-4-butanoic acid, x-[2-(3-[(diethylamino)carbonyl] phenyl]ethyl]-y-oxo-4'-(pentyloxy)-; [1,1'-Biphenyl]-4-butanoic acid, a-[2-(3-[(diethylamino)carbonyl] phenyl]ethyl]-y-oxo-4'-(phenylmethoxy)-; 1,2-Pyrrolidinedicarboxylic acid, 3-[(4'-chloro[1,1'-biphenyl] 10 4-yl)carbonyl]-, 1-(phenylmethyl) ester, (2S-trans)-; 1,2-Pyrrolidinedicarboxylic acid, 3-[(4'-chloro[1,1'-biphenyl] 4-yl)carbonyl]-, 1 -(phenylmethyl) ester, (2'R-trans)-; L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl] 1-[[(phenylmethyl)amino]carbonyl]-, trans-; 15 L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(1-oxo 3-phenylpropyl)-, trans-; L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(phenylacetyl)-, trans-; L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(3,3-dimethyl 20 1 -oxobutyl)-, trans-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-x-heptyl-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-decyl-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-nitro-y-oxo-ax-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 -cyano-'y-oxo-ax-(2-phenylethyl)-; 25 [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(2-iodophenyl)ethyl]-y oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3-iodophenyl)ethyl]-y oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-a.-[2-(4-iodophenyl)ethyl]-y 30 oxo-; WO 00/04892 PCT/US99/13948 -12 [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-x-[2-(3,5 dimethoxyphenyl)ethyl]-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-a-phenyl-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-a-(phenylmethyl)-; 5 [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-x-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-y-oxo-x-[(trimethylsilyl) methyl]-; [1,1'-Biphenyl]-4-butanoic acid, 4'-bromo-y-oxo-ax-(3-phenylpropyl)-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-a-(3-phenylpropyl)-; 10 [1,1'-Biphenyl]-4-butanoic acid, 4 '-amino-y-oxo-x-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-x-(2-phenylethyl)-4' [[(phenylmethoxy)carbonyl]amino]-; [1,1'-Biphenyl]-4-butanoic acid, 4'-[[(1,1-dimethylethoxy) carbonyl]amino] -y-oxo-x-(2-phenylethyl)-; 15 [1,1'-Biphenyl]-4-butanoic acid, 4 '-(acetylamino)-y-oxo-X (2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-[(I-oxopentyl)amino]-c (2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-[(3,3-dimethyl-1-oxobutyl)amino]-y 20 oxo-a-(2-phenylethyl)-; [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-methoxycarbonyl) phenyl] ethyl]-y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, a-[ 2 -(2-carboxyphenyl)ethyl]-4'-chloro y-oxo-; 25 [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-a-[2-[2-[(diethylamino) carbonyl)phenyl] ethyl] -y-oxo-; [1,1'-Biphenyl]-4-butanoic acid, 4 '-chloro-ax-[2-[3-[(diethylamino) carbonyl)phenyl]ethyl]-y-oxo-, (S)-; and [1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-[(diethylamino) 30 carbonyl)phenyl]ethyl]-y-oxo-,

(R)-.

WO 00/04892 PCT/US99/13948 -13 Fenbufen and compounds related to fenbufen can be utilized. Such compounds are described in United States Patent Number 3,784,701 and by Child, et al., J. Pharm. Sci., 1977;66:466-476, and Arzneim-Forsch, 1980;30(4A):695 702, all of which are incorporated herein by reference. Preferred compounds from 5 the fenbufen series to be utilized in this invention have the formula 00R , where Ris 0 CCH2CH 2 COOH (fenbufen), COCH=CHCOOH, S0 2

NH

2 , COCH2CHCOOH, 10

CH

3

COCH

2 CH-COOH 0 ,COCH 2

CH

2

SO

3 Na, CH(OH)CH 2

CH

2 COOH,

COCH

2 CHCOOH, COCH 2

CH

2 CONHOH, C(=NOH)CH 2

CH

2 COOH, and 15 OH

COCH

2

SCH

2 COOH. Numerous peptides are known matrix metalloproteinase inhibitors. Typical of such peptides are those described in United States Patent Number 5,300,501; 5,530,128; 5,455,258; 5,552,419; WO 95/13289; and WO 96/11209, all of which 20 are incorporated herein by reference. Such compounds are illustrated by the formula 0 R 1 2 0 R S N

NR

4

R

5 H

R

8 0 R 3 where each of the variable groups can include hydrogen alkyl, aryl, heteroaryl, alkenyl, alkynyl, carboxy, and the like. Preferred compounds from within this 25 class which can be utilized in the method of this invention include the following: WO 00/04892 PCT/US99/13948 -14 N-[2,3 -bis-Acetylmercaptopropanoyl]-L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-3 -methoxycarbonylpropanoyl]-L-leucyl-L phenylalanine N-methylamide; 5 N- [ 2 -Acetylmercapto-4-methoxycarbonybutanoyJ-L-leucyl-L phenylalanine N-methylamide; N-[2-Acetylmercapto-5-methoxycarbonylpentanoylpLleucyl-L phenylalanine N-methylamide; N-[2-Acetylmercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L 10 phenylalanine N-methylamide; N-[2-Acetylmercapto-4-phthalimidobutanoyl] -L-leucyl-L-phenylalanine N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; 15 N-[2-Acetylmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2,3 -bis-Mercaptopropanoyl]-L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-3 -methoxycarbonyipropanoyl] -L-Ieucyl-L-phenylalanine N-methylamide; 20 N- [2-Mercapto-4-methoxycarbonylbutanyol] -L-leucyl-L-phenylalanine N-methylamide; N- [2-Mercapto-4-methoxycarbonylpentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N-[2-Mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine 25 N-methylamide; N-[2-Mercapto-4-phthalimidobutanoyl] -L-leucyl-phenyl-alanine N-methylamide;

N-[

2 -Mercapto-5-phthalimidopentanoyl]-L-leucyli..phenylalanine N-methylamide; 30 N- [2-Mercapto-6-phthalimidohexanyoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [ 2 -Acetylmercapto-5-methoxycarbonylpentanoylyL-leucyl L-phenylalanine N-methylamide; WO 00/04892 PCT/US99/13948 -15 N- [ 2 -Acetylmercapto-6-methoxycarbonylhexanyolyL-leucyl. L-phenylalanine N-methylamide;

N-[

2 -Acetylmercapto-6-methoxycarbonylhexanyol] -L-valinyl L-phenylalanine N-methylamide; 5 N- [ 2 -Acetylmercapto-6-methoxycarbonylhexanyolyLleucyl-L-tryptophan N-methylamide;

N-[

2 -Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [ 2 -Acetylmercapto-5-phthalimidopentanoypLvaliny1L-pheny~alanine 10 N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [ 2 -Acetylmercapto-5-phthalimidopentanoyl]pL-eucyl.L [f3-(4 thiazolyl)]alaine N-methylamide; 15 N-[ 2 -Acetylmercapto-5-phthalimidopentanoylLeucyliL(p..(2 pyridyl)alanine N-methylamide; N- r2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-5-methyl-L glutamicacid N-methylamide; N- [ 2 -Acetylmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine 20 N-methylamide; N- [2-Acetylmercapto-2-(3 -phthalimido) phenylacetyl] -L-leucyl L-phenylalanine N-methylamide; N- [2-Mercapto-5 -methoxycarbonylpentanoyl] -L-phenylalanine N-methylamide; 25 N- [ 2 -Mercapto-6-methoxycarbonylhexanyol] -L-leucyl-L-phenylalanine N-methylamide;

N-[I

2 -Mercapto-6-methoxycarbonylhexanyo]-L-leucyl-L-trptophan N-methylamide; N- [2-Mercapto-5 -phthalimidopentanoyl] -L-leucyl-L-phenylalanine 30 N-methylamide; N- [2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; WO 00/04892 PCTIUS99/1 3948 -16 N- [2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L- [1 (4-thiazolyl)alanine N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L- [f-(2 pyridyl)] alanine N-methylamide; 5 N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyls -methyl-L-glutamic acid N-methylamide; N- [2-Mercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N-[N-Mercaptoacetyl)-L-leucyl]-L-phenylalanine N-methylamide; 10 N-[Acetomercaptoacyl)-L-leucyl-L-phenylalanine methylamide;

(RS)-

2 -(Acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-

2 -(Acetylthio)propanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-3 -methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; 15 (RS)- 2 -(Acetylthio)-2-phenylacety1-L-1eucypL-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-3 -phenylpropanoyl-L-1eucyI-L-phenylalanine N-methylamide;

(RS)-

2 -(Acetylthio)-4-phenylbutanoyl-L-1eucyl.L-phenylalanine 20 N-methylamide; N-(Acetylmercaptoacyl)-L-threonyl-L-phenylalanine methylamide; N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide;

(RS)-

2 -Mercaptopentanoyl-L-leucyl-L-phenylaanine N-methylamide;

(RS)-

2 -Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide; 25 (RS)- 2 -Mercapto-3-methylbutanoyl-L-leucyli..phenylalanine N-methylamide;

(RS)-

2 -Mercapto- 2 -phenylacetyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-3 -phenylpropanoyl-L-leucy-L-phenylalanine 30 N-methylamide;

(RS)-

2 -Mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; WO 00/04892 PCT/US99/13948 -17 N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide; N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide; [4-(N-Hydroxyamino)-2(R)-cyclohexylmethylsuccinyl]-L- cyclohexylalanine-N-(2-phenylethyl)amide; 5 [ 4 -N-(Hydroxyamino)-2R-isobutylsuccinyl]-L- -cyclohexylalanine-N (2-phenylethyl)amide;

[

4 -(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-$-cyclohexylalanine N-(2-phenylethyl)amide;

[

4 -(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L- -cyclohexylalanine 10 N-[2-(N,N-dimethylamino]ethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L- -cyclohexylalanine N-[2-(p-sulphonamidophenyl)ethyl)amide;

[

4 -(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L- -cyclohexylalanine N-(2-(p-sulphonylphenyl)ethyl)amide; 15 [ 4 -(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-$-cyclohexylalanine N-[2-(2-pyridyl)ethyl]amide; [4-(N-Hydroxyamino)-2R-pentylsuccinyl]-L- -cyclohexylalanine-N (2-phenylethyl)amide;

[

4 -(N-Hydroxyamino)-2R-isoamylsuccinyl]-L- -cyclohexylalanine-N 20 (2-phenylethyl)amide; [4-(N-Hydroxyamino)-2R-phenylbutylsuccinyl]-L- -cyclohexylalanine-N (2-phenylethyl)amide;

[

4 -(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-j-cyclohexylalanine N-[3-(4-morpholinyl)propyl]amide; 25 [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L- -cyclohexylalanine N-[P-alanine]amide;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L- -cyclohexylalanine amide; [4-(N-Hydroxyamino)-2R-(3-phenylpropyl)succinyl]-L- cyclohexylalanine amide; 30 [4-(N-Hydroxyamino)-2R-(3-phenylbutyl)succinyl]-L-$ cyclohexylalanine amide; WO 00/04892 PCT/US99/13948 -18 [4-N-(Hydroxyamino)-2R-phenylethylsuccinyl]yL..eucine-N (2-phenylethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl] -L-leucine-N (2-phenylethyl)amide; 5 [ 4 -(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-tryptophan amide; [4-(N-Hydroxyamino)-2(R)-isobutylsuccinylyL-valine amide; [3-Phosphono-2R,S-phenylpropyl- 1 -oxopropyl]-L-13-cyclohexylalanine-N (2-phenylethyl)amide, dimethylester; [3 -Phosphono-2R-phenylpropyl-l1-oxopropy1]-L-3-cyclohexylalanine-N 10 (2-phenylethyl)amide; [3 -Phosphono-2S-phenylpropyl-l1-oxopropyl] -L-f 3 -cyclohexylalanine-3 alanine; [3 -Phosphono-2R-phenylpropyl- I-oxopropyl] -L-f3-cyclohexylalanine; [3-Phosphono-2S-phenylpropyl-lI-oxopropyl]-L-p-cyclohexylalaninef3.. 15 alanine, methyl ester; [3-Phosphono-2R,S-phenylpropyl- I-oxopropyl]-L-J3-cyclohexylalanine-N

[

4 (3-aminopropyl)morpholine]amide, bromine salt; [3 -Phosphono-2R,S-(4-methylphenyl)propyl- I -oxopropyl]-L-3 cyclohexylalanine-N-(2-phenylethyl)amide, diethylester; 20 [3 -Phosphono-2R,S-(4-methylphenyl)propyl-lI-oxopropyl] -L-f3 cyclohexylalanine-N-(2-phenylethyl)-amide; 4-t-Butoxy-2(R)- [ 3

-(

2 -phenoxyethyl)succinyl]-L-f3-cyclohexylalanine-N (2-phenylethyl)amide; 4-Hydroxy-2(R)- [3 -(2-phenoxyethyl)succinyl] -L-f 3 -cyclohexylalanine-N 25 (2-phenylethyl)amnide; 4 -(N-Hydroxyamino-2(R)-[3-(2-phenoxyethyl)succinyl] -L-f0 cyclohexylalanine-N-(2-phenylethyl)amide; {4-Hydroxy-2(R)-[3-(4-pyridinium)propyl] succinyl }-L-J3 cyclohexylalanine-N-(2-phenylethyl)amide; 30 { 4 -(N-Hydroxyamino)-2(R)-[3-(4-pyridinium)propylsuccinyl -L-f3 cyclohexylalanine-N-(2-phenylethyl)amide; WO 00/04892 PCT/US99/13948 -19 {4-(N-Hydroxyamino)-2(R)-[ 3 -(N-methyl-4-pyridinium)propyl]succinyl} L-$-cyclohexylalanine-N-(2-phenylethyl)amide; {4-Hydroxy-2-(R)-[3-(4-methylphenyl)propyl]succinyl}

-L-$

cyclohexylalanine-N-[( 2 -morpholine-sulphonylamino)ethyl]amide; 5 {4-(N-Hydroxyamino)-2-(R)-[ 3

-(

4 -methylphenyl)propyl]succinyl}-L-$ cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide; {4-(N-Hydroxyamino)-2-(R)-[3-(4-chlorophenyl)propyl]succinyl}-L- cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide; {4-N-Hydroxyamino)-2-(R)-[3-( 4 -methylphenyl)propyl]succinyl}-L- 10 cyclohexylalanine-N-[(2-dimethylsulphonylamino)propyl]amide; [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L-[S (methyl)penicillamine]-N-methylamide; [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L-[S (methyl)penicillamine]amide; 15 [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L penicillamine]amide; {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-[S (methyl)penicillaminesulphone]-N-methylamide; {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L-[S 20 (methyl)penicillaminesulphoxide]-N-methylamide; {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L penicillamine-N-methylamide; [4-(N-Hydroxyamino)-2(R)-3-(2-methylpropyl)succinyl]-L-[S methyl)penicillamine]-N-methylamide; 25 N 4 -Hydroxy-NI -(1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-4 (chlorophenylpropyl)succinamide;

N

4 -Hydroxy-NI -(1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4 methylphenylpropyl)succinamide;

N

4 -Hydroxy-NI -(1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4 30 methoxyphenylpropyl)succinamide;

N

4 -Hydroxy-N1 -(1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4 trifluoromethylphenylpropyl)succinamide; WO 00/04892 PCT/US99/13948 -20

N

4 -Hydroxy-N 1 -(1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4 chloromethylphenylpropyl)succinamide; N-[N-(Mercaptoacetyl)-L-leucyl]-L-phenylalanine methylamide; N-(Acetomercaptoacyl)-L-leucyl]-L-phenylalanine methylamide; 5 (RS)- 2 -(Acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-

2 -(Acetylthio)propanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)-3-methylbutanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-

2 -(Acetylthio)-2-phenylacetyl-L-leucyl-L-phenylalanine 10 N-methylamide; (RS)-2-(Acetylthio)-3-phenylpropanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-

2 -(Acetylthio)-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; 15 N-(Acetylmercaptoacyl)-L-threonyl-L-phenylalanine methylamide; N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide;

(RS)-

2 -Mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-

2 -Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine 20 N-methylamide; (RS)-2-Mercapto-2-phenylacetyl-L-leucyl-L-phenylalanine N-methylamide;

(RS)-

2 -Mercapto-3-phenylpropanoyl-L-leucyl-L-phenylalanine N-methylamide; 25 (RS)- 2 -Mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine N-methylamide; N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide; N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide; N-[2,3-bis-Acetylmercaptopropanoyl]-L-leucyl-L-phenylalanine 30 N-methylamide;

N-[

2 -Acetylmercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L phenylalanine N-methylamide; WO 00/04892 PCT[US99/13948 -21 N-[2-Acetylmercapto-4-methoxycarbonylbutanoyl] -L-leucyl-L phenylalanine N-methylamide;

N-[

2 -Acetylmercapto-5-methoxycarbonylpentanoylpL-leucyl-L phenylalanine N-methylamide; 5 N- [ 2 -Acetylmercapto-6-methoxycarbonylhexanoyl]yL-Ieucyl-L phenylalanine N-methylamide;

N-[

2 -Acetylmercapto-4-phthalimidobutanoylpL-eucyl-Lphenylalanine N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine 10 N-methylamide; N-[2-Acetylmercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [2,3-bis-Mercaptopropanoyl] -L-leucyl-L-phenylalanine N-methylamide; N-[2-Mercapto-3 -methoxycarbonyipropanoyl] -L-leucyl-L-phenylalanine 15 N-methyl amide; N- [ 2 -Mercapto-4-methoxycarbonylbutanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [ 2 -Mercapto-5-methoxycarbonylpentanoylyLleucyl-Lphenylalanine N-methylamide; 20 N- [ 2 -Mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine N-methyl amide; N-[2-Mercapto-4-phthalimidobutanoyl] -L-leucyl-L-phenylalanine N-methylamide;

N-[

2 -Mercapto-5-phthalimidopentanoyl]-L-leucylL-phenylalanine 25 N-methylamide; N- [2-Mercapto-6-phthalimidohexanoyl] -L-leucyl-L-phenylalanine N-methylamide; N- [ 2 -Acetylmercapto-5-methoxycarbonylpentanoyl] -L-leucyl-L phenylalanine N-methylamide; 30 N-[ 2 -Acetylmercapto-6-methoxycarbonylhexanoylyL-leucyl-L phenylalanine N-methylamide;

N-[

2 -Acetylmercapto-6-methoxycarbonylhexanoyl] -L-valinyl-L phenylalanine N-methylamide; WO 00/04892 PCTIUS99/13948 -22 N- [ 2 -Acetylmercapto-6-methoxycarbonylhexanoy]yLeucy1L-tryptophan N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-phenylalanine N-methylamide; 5 N- [ 2 -Acetylmercapto-5-phthalimidopentanoylyL-valinypL-phenyalanine N-methylamide;

N-[

2 -Acetylmercapto-5-phthaimidopentanoy]pLeucy1Ltryptophan N-methylamide;

N-[

2 -Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-L-[3 10 (4-thiazolyl)] alanine N-methylamide; N- [2-Acetylmercapto-5-phthalimidopentanoyl]pL-eucyl1L.{P. (2-pyridyl)] alanine N-methylamide; N-[2-Acetylmercapto-5-phthalimidopentanoyl] -L-leucyl-5-methyl-L glutamic acid N-methylamide; 15 N- [ 2 -Acetylmercapto-6-phthalimidohexanoylyL-eucypL-phenylalanine N-methylamide; N- [ 2 -Acetylmercapto-2-(3-phthalimido)phenylacetyl]yL..eucyl-L phenylalanine N-methylamide; N- [ 2 -Mercapto-5-methoxycarbonylpentanoyl]L.leucyl-Lphenylaanine 20 N-methylamide; N- [ 2 -Mercapto-6-methoxycarbonylhexanoyl] -L-leucyl-L-phenylalanine N-methylamide;

N-[

2 -Mercapto-6-methoxycarbonylhexanoyl]yL-leucyl-L-tryptophal N-methylamide; 25 N- [ 2 -Mercapto-5-phthalimidopentanoyl]-L-leucylL-phenylalanine N-methylamide; .N- [ 2 -Mercapto-5-phthalimidopentanoyl] -L-leucyl-L-tryptophan N-methylamide; N- [ 2 -Mercapto-5-phthalimidopentanoy]yL-eucyl1L..[P 30 (4-thiazolyl)alanine N-methylamide; N-[2-Mercapto-5-phthalimidopentanoyl] -L-leucyl-L-[f3-(2-pyridyl)]alanine N-methylamide; WO 00/04892 PCTIUS99/13948 -23 N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L-glutamic acid N-methylamide; N-[2-Mercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine N-methylamide; 5 N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino] 3-methylbutanamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-3-picolyl)amino] 2-cyclohexylacetamide; N-Hydroxy-2(R)-[[ 4 -methoxybenzenesulfonyl]-(benzyl)amino] 10 4-methylpentanamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-6-[(N,N dimethylglycyl)amino]hexanamide hydrochloride; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino] 3-methylbutanamide; 15 N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(4-picolyl)amino] 2-cyclohexylacetamide; N-Hydroxy-2(R)-[( 4 -methoxybenzenesulfonyl]-(4-picolyl)amino] 2-(2-tetrahydrofuranyl)acetamide; N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-( 3 -picolyl)amino] 20 3-methylbutanamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N 2 -(S)-piperazic acid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N 2 -(s)_ piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thiophenylsuccinyl]-N 2 30 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thiobenzylsuccinyl]-N 2 (S)-piperazic acid N-methyl amide; WO 00/04892 PCT/US99/13948 -24 [4-(N-Hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]

N

2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylacetate]-N 2 -(S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl-isopropanoate]-N 2 -(s)_ piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N 2

-(S)

10 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl-thioisopropanoate]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(2-pyridyl)]-N 2

-(S)

piperazic acid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl-(3-pyridyl)]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(4-pyridyl)]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl thio-tert-butanoate]-N 2

-(S)

20 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylsuccinyl]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N 2 -(S)-piperazic acid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-hexyl-3S-methoxyphenylsuccinyl]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methoxybenzylsuccinyl]-N 2 -(s). piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methylthiophenylsuccinyl]-N 2 -(S)_ 30 piperazic acid N-methyl amide; WO 00/04892 PCT/US99/13948 -25 [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthiobenzylsuccinyl]-N 2 -(S)_ piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-(methylthio-2-thienyl)succinyl]-N 2 .. (S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl acetate]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methylisopropanoate]-N 2

-(S)

10 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl tert-butanoate]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methylthioacetate]-N 2 -(S)-piperazic acid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-hexyl-3S-methylthioisopropanoate]-N 2 _(S). piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methylthio-tert-butanoate]-N 2 .(S). piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(2-pyridyl)]-N 2 -(S)-piperazic 20 acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3 S-methyl-(3-pyridyl)]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(4-pyridyl)]-N 2 .(S)-piperazic acid N-methyl amide; 25 [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylsuccinyl]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methoxyphenylsuccinyl]-N 2 30 (S)-piperazic acid N-methyl amide; WO 00/04892 PCT/US99/13948 -26 [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methoxybenzylsuccinyl]-N 2 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthiophenylsuccinyl]-N 2 (S)-piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthiobenzylsuccinyl]-N 2 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-(methylthio-2-thienyl) succinyl]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N 2

-(S)

10 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methyl acetate]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylisopropanoate]-N 2

-(S)

piperazic acid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-ethylphenyl-3 S-methyl-tert-butanoate] -N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthioacetate]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthioisopropanoate]-N 2 20 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthio-tert-butanoate]-N 2 (S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N 2 -(S)-piperazic acid N-methyl aide; 25 [4-(N-Hydroxyamino)-2R-octyl-3S-methylthiophenylsuccinyl]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthiobenzylsuccinyl]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthio-2-thienyl)succinyl]-N 1 30 (S)-piperazic acid N-methyl amide; WO 00/04892 PCT/US99/13948 -27 [4-(N-Hydroxyamino)-2R-octyl-3S-methyl acetate]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylisopropanoate]-N 2 _(S)_ piperazic acid N-methyl amide; 5 [4-(N-Hydroxyamino)-2R-octyl-3S-methyl tert-butanoate]-N 2

-(S)

piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthioacetate]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methylthioisopropanoate]-N 2 -(S)_ 10 piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3 S-methylthio-tert-butanoate]-N 2 -(s)_ piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(2-pyridyl)]-N 2 -(S)-piperazic acid N-methyl amide; 15 [4-(N-Hydroxyamino)-2R-octyl-3 S-methyl-(3-pyridyl)]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(4-pyridyl)]-N 2 -(S)-piperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-N 2 -(S)-4'(S/R) 20 benzylpiperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-N 2 -(S)-5'(S/R) benzylpiperazic acid N-methyl amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N 2 -(S)-6'(S/R) benzylpiperazic acid N-methyl amide; 25 [ 4 -(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-N 2

-S)

[5',6']benzopiperazic acid N-methyl amide; N-[l(R)-Carboxy-ethyl]-ax-(S)-isobutylglycine-(S)-N 2 -piperazic acid methyl amide; N- [1 (R)-Carboxy-ethyl]-ax-(S)-hexylglycine-(S)-N 2 -piperazic acid methyl 30 aide; WO 00/04892 PCT/US99/13948 -28 N-[ 1 (R)-Carboxy-ethyl] -a-(S)-heptylglycine-(S)-N 2 -piperazic acid methyl amide; N-[1(R)-Carboxy-ethyl]-a-(S)-octylglycine-(S)-N 2 -piperazic acid methyl amide; 5 N-[I(R)-Carboxy-ethyl]-a-(S)-ethylphenylglycine-(S)-N 2 -piperazic acid methyl amide; N-[1(R)-Carboxy-ethyl] -a-(S)-propylphenylclycine-(S)-N 2 -piperazic acid methyl amide; N-[(R)-Carboxy-ethylthiobenzyl]-a-(S)-isobutylglycine-(S)-N 2 -piperazic 10 acid methyl amide; N-[ I(R)-Carboxy-ethylthiobenzyl]-a-(S)-hexylglycine-(S)-N 2 -piperazic acid methyl amide; N-[1(R)-Carboxy-ethylthiobenzyl]-a.-(S)-ethylphenylglycine-(S)-N 2 . piperazic acid methyl amide; 15 N-[1(R)-Carboxy-ethylthiobenzyl]-a-(S)-propylphenylglycine-(S)-N 2 piperazic acid methyl amide; N-[l(R)-Carboxy-ethyloxybenzyl]-a-(S)-isobutylglycine-(S)-N 2 -piperazic acid methyl amide; N-[l(R)-Carboxy-ethyloxybenzyl]-a-(S)-hexylglycine-(S)-N 2 -piperazic 20 acid methyl amide; N-[1(R)-Carboxy-ethyloxybenzyl]-ax-(S)-ethylphenylglycine-(S)-N 2 piperazic acid methyl amide; N-[l(R)-Carboxy-ethyloxybenzyl]-a-(S)-propylphenylglycine-(S)-N 2 piperazic acid methyl amide; 25 N-[1(R)-Carboxy-4-(p-toluenesulfonyl)butyl]-a-(S)-phenethylglycyl-(S)

N

2 -piperazic acid methyl amide; N-[ 1(R)-Carboxyethyl]-x-[2-(4-phenylphenoxy)ethyl]-glycyl-(S)-N 2 piperazic acid methyl amide; 2-[2(R)-[2-[ 1,1 '-Biphenyl)yl]ethyl]-4-butyl-4(S)-carboxy-1 -oxobutyl] 30 3(S)-methylaminocarbonyl-hexahydropyridazine; WO 00/04892 PCTIUS99/13948 -29 2-[2(R)-[2-[ 1,1 '-Biphenyl)yl]ethyl]-4-methyl-4(S)-carboxy-1 -oxobutyl] 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-[ 1,1 '-Biphenyl)yl]propyl]-4-butyl-4(S)-carboxy- I -oxobutyl] 3(S)-methylaminocarbonyl-hexahydropyridazine; 5 2-[ 2 (R)-[2-(4-Propylphenyl)ethyl]-4-butyl-4(S)-carboxy- 1 -oxobutyl]-3(S) methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-(4-Butylphenyl)ethyl]-4-butyl-4(S)-carboxy- I -oxobutyl]-3(S) methylaminocarbonyl-hexahydropyridazine; 2-[2(R)-[2-(4-t-Butylphenyl)ethyl]- 4 -butyl-4(S)-carboxy- I -oxobutyl] 10 3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2-[4-(4-Fluorophenyl)phenyl]ethyl] -4-butyl-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2- [4-(4-Fluorophenyl)phenyl] ethyl] - 4 -methyl-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 15 2-[2(R)-[ 2 -n-Octyl-4-methyl-4(S)-carboxy- I -oxobutyl]-3(S) methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2- [(4-Thiazolyl)phenyl]ethyl] -4-butyl-4(S)-carboxy- I -oxobutyl] 3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2- [(4-Thiazolyl)phenyl] ethyl] -4-methyl-4(S)-carboxy 20 1 -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2- [(4-Thiazolyl)phenyl] ethyl] -4- [3 -(phenylsulfonyl)propyl-4(S) carboxy- I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2-[(4-Thiazolyl)phenyl]ethyl]-4-(3 -phenylpropyl)-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 25 2- [2(R)- [2- [( 4 -Oxazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy- I -oxobutyl] 3(S)-methylaminocarbonyl-hexahydropyridazine; 2-[2(R)- [2- [(4-Oxazolyl)phenyl] ethyl]-4-methyl-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2-[(4-Oxazolyl)phenyl]ethyl] -4- [3 -(phenylsulfonyl)propyl-4(S) 30 carboxy- 1 -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)-[2- [(4-Oxazolyl)phenyl]ethyl] -4-(3 -phenylpropyl)-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; WO 00/04892 PCT/US99/13948 -30 2- [2(R)- [ 2

-[

4 -(Dimethylamino)methylpheny1] ethyl] -4-butyl-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2- [4-(Dimethylamino)methylphenyl] ethyl] -4-methyl-4(S) carboxy- I -oxobutyl] -3 (S)-methylaminocarbonyl-hexahydropyridazine; 5 2- [2(R)- [2- [4-(Dimethylamino)methylphenyl] ethyl] -4-[3 (phenylsulfonyl)propyl-4(S)-carboxy- 1 -oxobutyl]-3 (S)-methylaminocarbonyl hexahydropyridazine; 2- [2(R)- [2- [ 4 -(Dimethylamino)methylphenyl] ethyl] -4-(3 -phenyipropyl) 4(S)-carboxy- I -oxobutyl]-3 (S)-methylaminocarbonyl-hexahydropyridazine; 10 2-[2(R)- [2- [(4-Imidazolyl)phenyl] ethyl] -4-butyl-4(S)-carboxy I -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2 -[2(R)- [2- [(4-lmidazolyl)phenyl] ethyl] -4-methyl -4(S)-carboxy 1 -oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2 -[(4-Imidazolyl)phenyl] ethyl] -4- [3 -(phenylsulfonyl)propyl-4(S) 15 carboxy- I -oxobutyl] -3 (S)-methylaminocarbonyl-hexahydropyridazine; 2- [2(R)- [2- [(4-lmidazolyl)phenyl] ethyl] -4- [3 -(phenylpropyl)-4(S) carboxy- I -oxobutyl]-3 (S)-methylaminocarbonyl-hexahydropyridazine;

HS(CH

2

)

2 -(S-D-Leu)-Phe-NHMe; HS(S)CHMeCH 2 -(S-D-Leu)-Phe-NHMe; 20 HS(S)CH(PhtNBu)CH 2 -(S-D-Leu)-Phe-NHMe; HS(S)CH(PhtNEt)CH 2 -(S-D-Leu)-Phe-NHMe; HS( 1,2-Cyclopentyl)(S-D-Leu)-Phe-NHMe Me-S(NH)2-(CH 2 -DL-Leu)-Trp-NHBn; n-Bu-S(NH) 2

-(CH

2 -DL-Leu)-Trp-NHBn; 25 n-Bu-S(NH)2-(CI- 2 -DL-TyrOCH 3 )-Trp-NHBn; Me-RS-SO(NH)-(CH 2 -L-Leu)-Phe-Ala.NH 2 ; n-Bu-RS-SO(NH)-(CH 2 -L-Leu)-Phe-Ala-NH 2 ;

HONH-C-CH

2

CH(CH

2

CH(CH

3

)

2 )-CO-Nal-Ala.NH 2 ; 30 0 HO-NH-CO-CH2-CH-(CH 2

-CH(CH

3

)

2 -CO-Na[-Pro-NH 2

;

WO 00/04892 PCT/US99/13948 -31 HO-NH-CO-CH(CH3-CH(CH 2

)-CH(CH

3

)

2 )-CO-Nal-Ala-NH 2 ; H HON- COCH2 -C-CO-Pal-Ala-NH 2 , wherein Pal is 3-pyridylalanine; H H HON-COCH2-C-CO-Nal(CH 2 S)Ala-NH2 5 HO-NH-CO-CH2-CH(CH2CH(CH 3

)

2 )-CONal-(CH2NH)-Ala-NH 2 ; O 0 H HOs N H

NH

2 0

-

'g 0 00 O 0 HOsN N NHEt f N H H O 0 O O HONHC-

CH

2 -CHC-N-

CHCH

2

SCHCONH

2 I H CH 2 CH 2

CH

3 CH

(CH

3

)

2 WO 00/04892 PCT/US99/13948 -32 0 0 0 NONH-C-

CH

2 -- CHC-NH-CHC--NH-

CH

2 - CONH 2

CH

2 CH 2 CH 3 CH

(CH

3

)

2 0

OCH

3

OCH

3 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[(2-morpholin-4-ylethyl)amino] carbonyl] butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 5 1-(S)- [ [methylamino]carbonyl]butyl] amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[[(1 H-imidazol-2-ylmethyl)amino] carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [[(1 H-tetrazol-5-ylmethyl)amino]carbonyl]butyl] amino] -butanoic acid; 10 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[[(2-(phenyl)ethyl]amino] carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [ [(pyridin-3 -ylmethyl)amino]carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 15 1 -(S)-[[( 2 -methyl-2H-tetrazo-5-ylmethyl)amino]carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[[( 4 -hydroxy- 2 -methyl-pyrimidin-5-ylmethyl)amino]carbonyl]butyl] amino]-butanoic acid; 20 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [ [[2-(2-pyridin-3 -yl)ethyl] amino] carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [[1 -(1 H-tetrazol-5-yl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid; WO 00/04892 PCT/US99/13948 -33 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(5-amino-4H-[ 1, 2

,

4 ]-triazol-3-ylmethyl)amino] carbonyl]butyl]amino] butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 5 1 -(S)-[[[ I -(6-oxo- 1,6-dihydro pyridazin-3 -yl)ethyl] amino] carbonyl]butyl] amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(phenyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 10 1-(S)- [ [(benzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [[(pyridin-4-ylmethyl)amino] carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[[2-(1 H-imidazol-4-yl)ethyl]amino] carbonyl]butyl]amino] -butanoic acid; 15 4-(1,3-Dihydro-1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[(pyridin-2-ylmethyl)amino]carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[ [( 4 -sulfamoyl-phenyl)amino]carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 20 1-(S)- [[(3 -sulfamoyl-phenyl)amino] carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[( 4 -dimethylamino-benzyl)amino]carbonyl] butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [[[1 -(S)-phenyl-ethyl] amino] carbonyl]butyl] amino]-butanoic acid; 25 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[( 1,1 -dioxo-tetrahydro-thiophen-3-yl)amino]carbonyl]butyl]amino] butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[(4-sulfamoyl-benzyl)amino] carbonyl]butyl]amino] -butanoic acid; 30 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[[1-(R)-phenyl-ethyl]amino]carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[(3 -fluorobenzyl)amino]carbonyl] butyl] amino] -butanoic acid; WO 00/04892 PCT/US99/13948 -34 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[(furan-2-ylmethyl)amino] carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[(1-methyl-i H-tetrazol-5-ylmethyl)amino] carbonyl]butyl] amino]-butanoic 5 acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(1,2,3,4-tetrahydro-naphthalen- 1 -yl)amino]carbonyl]butyl] amino] butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 10 1-(S)- [ [(2,4-difluoro-benzyl)amino] carbonyl]butyl] amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[(3 -nitrobenzyl)amino] carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [ [( 4 -nitrobenzyl)amino]carbonyl]butyl]amino] -butanoic acid; 15 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [[( 4 -methanesulfonylamino-benzyl)amino]carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)- [ [( 3 -methanesulfonylamino-benzyl)amino]carbonyl]butyl] amino] -butanoic 20 acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[(3,4-difluoro-benzyl)amino] carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[( 3 -trifluoromethyl-benzyl)amino] carbonyl]butyl] amino] -butanoic acid; 25 4-[2-(S)- [1 -(R)-Carboxy-3-(1,3-dioxo- 1,3-dihydro-benzo[f]isoindol-2-yl) propylamino]- 4 -methyl-pentanoylamino-methyl)-benzoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(2-hydroxy- 1,1 -bis-hydroxymethyl-ethyl)amino]carbonyl]butyl]amino] butanoic acid; 30 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[ [(3,5-difluoro-benzyl)amino] carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1, 3 -dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [[benzylmethyl-amino] carbonyl] butyl]amino]-butanoic acid; WO 00/04892 PCTIUS99/13948 -35 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(2-dimethylaminoethyl)-methyl-amino] carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 5 1 -(S)- [[(1 -azabicyclo [2.2.2]-oct-3 (R)-amino]carbonyl]butyl] amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[[(1 -azabicyclo[2.2.2]oct-3 -(S)-yl)amino]carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 10 1 -(S)-[[(3-(R)- 4 -(S)-5-(R)- 6 -tetrahydrox-tetrahydra-pyran-2-(R)-ylmethyl)amino] carbonyl]butyl] amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [ [(N,N'-dimethyl-hydrazino)carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[fjisoindol-2-yl)-2-(R)-[[3-methyl 15 1-(S)-[[(methylmethoxy)amino]carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)- [ [(dimethyl)amino] carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(2-oxo-tetrahydro-thiophen-3 -(R)-yl)amino] carbonyl]butyl] amino] 20 butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)- [ [(2-oxo-tetrahydro-thiophen-3 -(S)-yl)amino] carbonyl]butyl] amino] butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 25 1 -(S)-[[(3-(R)-acetylamino-4-(S)-5-(S)-dihydroxy-6-(R)-hydroxymethyl tetrahydro-pyran-2-yl)amino] carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[[benzyl(2-hydroxyethyl)amino] carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 30 1 -(S)- [3,4-dihydro- I H-isoquinoline-2-carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[4-methylpiperazine- I -carbonyl]butyl]amino]-butanoic acid; WO 00/04892 PCT/US99/13948 -36 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[ I -oxo-[ 1, 4 ]thiazinane-4-carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[morpholine-4-carbonyl]butyl]amino]-butanoic acid; 5 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[4-(2-3-dihydroxy-propyl)-piperazine- I -carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[3,4,5,6-tetrahydro-H-[2,3]bipyridinyl- 1 ]carbonyl]butyl]amino] -butanoic 10 acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[(1 -methyl-8-oxo- 1, 7 -diazacyclotridec-9-yl)amino]carbonyl]butyl]amino] butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 15 1 -(S)-[ [methyl-i -methyl-piperidin-4-yl)amino]carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[(4-hydroxy-1,1-dioxo-tetrahydro-thiophen-3-yl)amino]carbonyl]butyl] amino]-butanoic acid; 20 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-(4-ethoxycarbonylmethyl-piperazine- I -carbonyl)butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[( 1,1 -dioxo-tetrahydro-thiophen-3-yl)-methyl-amino]carbonyl]butyl] 25 amino]-butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)- [2-(R)-(pyridin-3 -yl)-pyrrolidinecarbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[flisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[ 2 -(S)-(pyridin-3-yl)-pyrrolidinecarbonyl]butyl]amino]-butanoic acid; 30 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[3-oxo-2-(R)-phenyl-piperazine-1-carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[fisoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[ 3 -oxo-2-(S)-phenyl-piperazine-1-carbonyl]butyl] amino]-butanoic acid; WO 00/04892 PCTIUS99/13948 -37 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)- [(pyridine-3-carbonyl-hydrazino)carbonyl]butyl] amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1-(S)-[[(benzenesulfonyl)amino]carbonyl]butyl]amino] -butanoic acid; 5 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(3 -aminobenzyl)amino]carbonyl]butyl]amino]-butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)- [[4-(trifluoro-methanesulfonylamino)benzyl]amino] carbonyl]butyl]amino] butanoic acid; 10 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 1 -(S)-[ [[2-hydroxy-(R)-bicyclo [4.3.0]nona-3,6(1 )-diene]amino] carbonyl]butyl] amino]-butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[fjisoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[[2-hydroxy-(S)-bicyclo [4.3.0]nona-3,6(1)-diene] amino] carbonyl]butyl] 15 amino]-butanoic acid; 4-(1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl I -(S)-[[(N-methyl-pyrrolidine)-methyl-amino]carbonyl]butyl]amino] -butanoic acid; 4-(1,3-Dihydro- 1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl 20 1 -(S)-[(N-ethoxycarbonylmethyl-piperazine)- I -carbonyl]butyl] amino] -butanoic acid; 2-(R)-[ I -(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-bromo 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[1 -(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-propoxy 25 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[I -(S)-(Benzylamino)carbonyl-3-methylbutylamino] -4-(5-nitro 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[1 -(S)-(Benzylamino)carbonyl-3 -methylbutylamino]-4-(5-amino 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 30 2-(R)-[1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-methyl 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[]-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-methoxy 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; WO 00/04892 PCT/US99/13948 -38 2-(R)-[ I -(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5 benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-phenyl 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 5 2-(R)-[1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(1,3-dioxo 1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[I -(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5 methanesulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[I-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5 10 benzenesulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[ I -(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-hydroxy 1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid; 2-(R)-[[3-Methyl-1-(S)-[[(pyridin-3-ylmethyl)amino]carbonyl] butyl] amino] -4-(1,3,5,7-tetraoxo-3,5,6-tetrahydro- 1 H-pyrolo [3,4-f]isoindol 15 2-yl)butanoic acid; EtONHCONMe-CH 2 CH(iBu)-CO-L-Trp-NHEt; EtCONOH-CH2CH(iBu)-CO-L-Trp-NHEt; n-PrCONOEt-CH 2 CH(iBu)-CO-L-Trp-NHEt; EtNHCONOMe-CH 2 CH(iBu)-CO-L-Trp-NHEt; 20 MeNHCONOH-CH2CH(iBu)-CO-L-Trp-NHEt; EtONHCONMe-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; EtCONOH-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; n-PrCONOEt-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; EtNHCONOMe-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt; 25 MeNHCONOH-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;

HONHCONHCH

2 CH(iBu)-CO-L-TrpNHMe;

HONHCONHCH

2

CH

2 CH(iBu)-CO-L-TrpNHMe; HONHCONHCH(iBu)-CO-L-TrpNHMe; H2NCON(OH)CH(iBu)-CO-L-TrpNHMe; 30 N(OH)CH2CH(iBu)-CO-L-TrpNHMe; WO 00/04892 PCT/US99/13948 -39 H2NCON(OH)CH 2 CH2CH(iBu)-CO-L-TrpNHMe;

CH

3 CON(OH)CH(iBu)-CO-L-TrpNHMe;

CH

3

CON(OH)CH

2 CH(iBu)-CO-L-TrpNHMe;

CH

3

CON(OH)CH

2

CH

2 CH(iBu)-CO-L-TrpNHMe; 5 NHOHCOCH 2 CH(i-Bu)CO-L-Trp-NHMe;

HONHCONHCH

2 CH(i-Bu)CONHCHCOOH or R4

ROOCCH

2 CH(i-Bu)CONHCHCOOH; 10 R4 N-{ D,L- 2 -(Hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-(2' naphthyl)alanyl-L-alanine, 2-(amino)ethyl amide; N- { D,L- 2 -(Hydroxyaminocarbonyl)methyl-4-methylpentanoyl } -L 15 3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide; 4(S)- [3-Hydroxyaminocarbonyl-2(R)-(2-methylpropyl)propanoyl] amino 1,2,3,4,5-tetrahydro-3H-2-benzazepin-3-one; [4-(N-Hydroxyamino)-(2R)-isobutyl-3-methylsuccinyl]-L-phenylglycine N-methylamide; 20 4(S)-[2(R)-[1(R)-Hydroxycarbamoyl-2-morpholinoethyl] 4-methylvaleryl] amino-1,2,4,5-tetrahydro-3 H-2-benzazepine-3 -one; (1R, 4

S)-

4 -[(2R)-Hydroxycarbamoylmethyl-4-methylvaleryl]amino-3-oxo 1,2,4,5-tetrahydro-3H-2-benzazepine-1-carboxylic acid; 3

-[

2 -(N-Methylcarbamoyl)ethylsulfinyl]-5-methylhexanohydroxamic acid; 25 N-[( 2 -Thenoylmercapto-3-methyl)-butanoyl]-homocysteine thiolactone; N-[1(R)-Carboxy-ethyl]-ax-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide; N-[l(R)-Carboxy-ethyl]-a-(S)-( 2 -phenyl-ethyl)glycine-(L)-isoleucine, N-phenylamide; 30 N-[l(R)-Carboxy-ethyl]-a-(S)-( 2 -phenyl-ethyl)glycine-(L)-alanine, N-phenylamide; WO 00/04892 PCT/US99/13948 -40 N-[ I(R)-Carboxy-ethyl]--(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide; N-[1 (R)-Carboxy-ethyl]-a-(S)-( 2 -phenyl-ethyl)glycine-(L)-serine-O benzyl ether, N-phenylamide; 5 N-[1 (R)-Carboxy-ethyl]-x-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan, N-phenylamide; N-[l (R)-Carboxy-ethyl]-ax-(S)-(2-phenyl-ethyl)glycine-a-(S)-(2-phenyl ethyl)glycine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-norleucine, 10 N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-ca-(S)-( 2 -phenyl-ethyl)glycine-(L)-valine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-a-(S)-( 2 -phenyl-ethyl)glycine-(L)-serine, N-phenylamide hydrochloride; 15 N-[1(R)-Carboxy-ethyl]-a-(S)-( 2 -phenyl-ethyl)glycine-(L)-asparagine, N-phenylamide; N-[1 (R)-Carboxy-ethyl]-ax-(S)-(2-phenyl-ethyl)glycine-(L)-threonine, N-phenylamide hydrochloride; N-[ I (R)-Carboxy-ethyl]-a-(S)-( 2 -phenyl-ethyl)glycine-(L)-lysine, 20 N-phenylamide; N-[1(R)-Carboxy-ethyl]-ca-(S)-( 2 -phenyl-ethyl)glycine-(L)-glutamic acid, N-phenylamide; N-[1(R)-Carboxy-ethyl]-ax-(S)-( 2 -phenyl-ethyl)glycine-(L)-tyrosine, N-phenylamide hydrochloride; 25 N-[1(R)-Carboxy-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl ethyl)glycine-(L)-leucine, N-phenylamide; N-[1 (R)-Carboxy-5-(1 -oxo-isoindolin-2-yl)pentyl]-ax-(S)-(2-phenyl-ethyl) glycine-(S)-leucine, N-phenylamide hydrochloride; N-[1 (R)-Carboxy-5-(1 -oxo-isoindolin-2-yl)pentyl] -c-(S)-(2-phenyl-ethyl) 30 glycine-(S)-arginine, N-phenylamide; WO 00/04892 PCTIUS99/13948 -41 N-[ 1 (R)-Carboxy-ethyl]-c-(S)-(2-(3-hydroxyphenyl)-ethyl)glycine-(S) leucine, N-phenylamide hydrochloride; N-[1(R)-Carboxy-ethyl]-ax-(S)-(2-(4-methylphenyl)-ethyl)glycine-(S) leucine, N-phenylamide hydrochloride; 5 N-[ 1 (R)-Carboxy-ethyl]-ax-(S)-(2-(2'-thienyl)ethyl)glycine-(L)-leucine, N-phenylamide; N-[ I (R)-Carboxy-ethyl]-a-(S)-(2-(4-ethylphenyl)ethyl)glycine-(L) leucine, N-phenylamide; N-[1(R)-Carboxy-5-(I-oxo-isoindolin-2-yl)pentyl] -a-(S)-(2-(4 10 propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide; N-[1(R)-Carboxy-ethyl]-a-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L) leucine, N-phenylamide; N-[l (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-X-(S) (2-cyclohexyl-ethyl)glycine, N-phenylamide; 15 N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S) (cyclohexyl)glycine, N-phenylamide; N-[ 1 (R)-Carboxy-ethyl]-ax-(S)-(2-phenyl-ethyl)glycine-a-(S) (cyclohexylmethyl)glycine, N-phenylamide; N-[1(R)-Carboxy-ethyl]-x-(S)-(2-phenyl-ethyl)glycine-(L)- 20 naphthylalanine, N-phenylamide; N-[1 (R)-Carboxy-ethyl]-ax-(S)-(2-phenyl-ethyl)glycine-(L)-a naphthylalanine, N-phenylamide; N-[ I (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, ax,8-bis-N-phenylamide; 25 N-[l (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-cyclohexylamide; N-[(1(R)-Carboxy-ethyl)]-ca-(S)-(2-phenyl-ethyl)glycine-a-(S) (4-hydroxyphenyl-ethyl)glycine, N-phenylamide; N-[l (R)-Carboxy-ethyl]-x-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, 30 N-phenylamide; WO 00/04892 PCTIUS99/13948 -42 N-[ 1(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethy)gycine(L)glutmic acid, N8-benzylamnide, Noc-phenylamide; N-[ I (R)-Carboxy-ethyl]-ca-(S)-(2-pheny1-ethyl)gycine(L)-omithine, N-phenylamide; 5 N-[El(R)-Carboxy-ethyl] -cc-(S)-( 2 -phenyl-ethyl)glycine-(L)-arginine, N-phenylamide; N-[ 1 (R)-Carboxy-ethy1]-a-(S)-(2-phenyl-ethyl)gycinea.(S) (3 -phenylpropyl)glycine, N-phenylamide; N-El (R)-Carboxy-ethyl]-cx-(S)-(2-pheny1-ethyl)glycine..c-(S-n 10 octyiglycine, N-phenylamide; N-[ I (R)-Carboxy-ethyl] -c-(S)-( 2 -pheny1-ethy1)glycine-(L)-leucine, N-(4-carboxyphenyl)amide; N-[i (R)-Carboxy-ethyl]-cz-(S)-(2-phenyl-ethy1)glycine-(L)-leucine, N-(4-trifluoromethylphenyl)amide; 15 N-[ 1(R)-Carboxy-ethyl] -o-(S)-( 2 -phenyl-ethyl)glycine-(L)-leucine, N-(3 -pyridyl)amide; N- El (R)-Carboxy-ethyl] -1x-(S)-( 2 -phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl)amide; N-El (R)-Carboxy-ethyl]-ci-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L) 20 leucine, N-phenylamide; N- El (R)-Carboxy-ethyl] -a-(S)-(2-4-propylphenyl)ethyl)glycine-(L) arginine, N-phenylamide; N-El (R)-Carboxy-ethyl]-ux-(S)-(2-(3,4-dimethylphenyl-ethy1)glycine-(L) leucine, N-phenylamide; 25 (2-(((4-( 1,3 -Dihydro- 1,3 -dioxo-2H-isoindol-2-yl)butyl) hydroxyphosphinyl)methyl)-4-phenylbutanoyl).L-leucine, N-phenylamide; (2-(((4-( 1,3-Dihydro-l1-oxo-2H-isoindol-2-yl)butyl) hydroxyphosphinyl)methyl)-4-phenylbutanoyl)>Uieucine, N-phenylamide; (2-(((4-( 1,3-Dihydro- I -oxo-2H-isoindol-2-yl)butyl)(2-methyl 30 1 -(1I -oxopropoxy)propoxy)phosphinyl)methyl>4-phenylbutanoyl>L-leucine, N-phenylamide; WO 00/04892 PCTIUS99/13948 -43

(

2 -((Hydroxy(methyl)phosphinyl)methyl)-4-phenylbutanoyl)ii-eucine, N-phenylamnide; [[Hydroxy[ 1 (R)- [N-(N-acetyl-L-prolyl-L-alanyl)-amino] ethyl] phosphinyl] -methyl]-4-phenyl-butanoyl-L-leucyl, N-phenylamide; 5 [Hydroxy-[IN-(N-(benzoyl)-L-proly1)aminobuty1]phosphiny]methyl] 4-phenyl-butanoyl-L-leucine, N-phenylamide; [Ilydroxy-[ 2 -Methylpropyloxycarbonyl-aminobutyl]yphosphinyl]methyl] 4-phenylbutanoyl-L-leucine, N-phenylamide; [Hydroxy-[ 1-Methylethylamiinocarbonyl-aminobutyl] -phosphinyl]methyl] 10 4-phenylbutanoyl-L-leucine, N-phenylamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucinamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-phenylamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-benzylamide; N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-(2-phenylethyl)amide; 15 N-( 2 -Thiomethyl-4-phenylbutanoyl)-(L)-phenylalaninamide;

N-(

2 -Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine N-phenylamide;

N-(

2 -Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine N-benzylamide;

N-(

2 -Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine-balanine; 2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)- 1,5 -pentanedioie acid 1 -(L-leucine, 20 N-phenylamide)amide; 2(R)-(2-(4-( I -n-Propyl)phenyl)ethyl)- 1 ,5-pentanedioic acid 1 -(2(S)-t butyl)glycine, N-phenylamide)amide; 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)- 1 ,5-pentanedioic acid 1 -(2(S)-t butyl)glycine, N-(4-pyridylamide)amide; 25 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)- I ,5-pentanedioic acid 1 -(L-arginine, N-methylamide)amide; 2(BR)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-methyl- 1 ,5-pentanedioic acid I -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-methyl- 1,5-pentanedioic acid 30 1 -(2(S)-t-buty1)glycine, N-phenylamide)amide; 2(R)-(2-(4-( I-n-Propyl)phenyl)ethyl)-4-methyl- 1,5-pentanedioic acid I -( 2

(S)-(

4 -thiazolylmethy1)glycine, N-phenylamide)amide; WO 00/04892 PCT[US99/13948 -44 2(BR)-(2-(4-( I-n-Propyl)phenyl)ethyl)-4-methyl- 1,5-pentanedioic acid I -(2CS)-(3-pyridylmethyl)glycine, N-phenylamide)amide; 2LR)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-methyl- I ,5-pentanedioic acid 1 -(L-leucine, N-(4-pyridyl)amide)amide; 5 2 (BR)-(2-(4-(1-n-Propy1)pheny1)ethy1)-4-methy-1 ,5-pentanedioic acid I -( 2 (S)-(2-pyridylmethyl)glycine, N-phenylamide)amide; 2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-methyl- 1,5-pentanedioic acid I -(L-arginine, N-phenylamide)amide; 2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-methyb I ,5-pentanedioic acid 10 1 -(L-phenylalanine, N-4-pyridylamide)amide; 2(3R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-(

I-(

4 -(N-(2-oxoisoindolinyl)) butyl))- 1 ,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(BR)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)-4-(

I-(

4 -(N-(2-oxoisoindolinyl))-but 2-enyl))- 1 ,5-pentanedioic acid I -(L-leucine, N-phenylamide)amide; 15 2

(BR)-(

2

-(

4 -(4-Fluorophenyl)phenyl)ethy1)-4-methyl-.1 ,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2 (R)-(2-(4-(Phenyl)phenyl)ethyl)-4-methyl. 1 ,5-pentanedioic acid 1 -(L leucine, N-phenylamide)amide; 2

(R)-(

2 -(4-(4-Methoxyphenyl)phenyl)ethyl)-4-methyl. I ,5-pentanedioic 20 acid 1 -(L-leucine, phenylamide)amide; 2

(R)-(

2

-(

4 -(4-Methylphenyl)phenyl)ethyl)>4methyl I ,5-pentanedioic acid 1 -(L-Ieucine, phenylamnide)amide; 2

(R)-(

2

-(

4

-(

4 -Hydroxy-n-buty1)-phenyl)-ethyl)4-methylpentanedioic acid 1 -(S-leucine, phenylamide)amnide; 25 2

(R),

4

CS)-(

2

-(

4

-(

3 -Hydroxy-n-propyl)phenyl)ethy1-4-methy.. I ,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(3R)-(2-Phenylethyl)-4-methy1- 1,5-pentanedioic acid I -(L-Ieucine, N-phenylamide)amide; 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)- 1 ,5-pentanedioic acid I -(L-leucine, 30 N-ethylamide)amide; 2(R)-(2-(4-( 1 -n-Propyl)phenyl)ethyl)- I ,5-pentanedioic acid 1 -(L-leucine, N-isopropylamide)amide; WO 00/04892 PCT/US99/13948 -45 2(R)-(2-(4-(1-n-Propyl)phenyl)propyl)-1,5-pentanedioic acid 1-(2(S)-tert butyl-glycine, N-4-pyridyl)amide)amide; 2(R)-(3-(4-(1-n-Propyl)phenyl)propyl)-1,3-pentanedioic acid 1-(L-leucine, N-phenylamide)amide; 5 2(R)-(2-(4-(I-n-Propyl)phenyl)ethyl)-4-hexyl-1,5-pentanedioic acid 1-(L leucine, N-phenylamide)amide; 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-butyl-1,5-pentanedioic acid 1-(L leucine, N-phenylamide)amide; 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-(3-methylbenzyl)-1,5-pentanedioic 10 acid I -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-(2-benzimidazolyl)butyl) 1,5-pentanedioic acid 1-(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-(2-benzthiazolyl)butyl) 1,5-pentanedioic acid 1-(L-leucine, N-phenylamide)amide; 15 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-(2-benzoxazolyl)butyl) 1,5-pentanedioic acid 1 -(L-leucine, N-phenylamide)amide; 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid I -(L-leucine, N-phenylamide)amide 9-piperidineamide; 2(R)-(2-(4-(I-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid 1-(L 20 leucine, N-methylamide)amide 9-phenylamide; 2(3)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-carboxy- 1,9-nonanedioic acid 1 -(L-leucine, N-methylamide)amide 9-tert-butylamide; 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid I -(L-leucine, N-methylamide)amide 9-benzylamide; 25 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid I -(L-leucine, N-methylamide)amide 9-morpholineamide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-carboxy- 1,9-nonanedioic acid I -(L-leucine, N-methylamide)amide 9-(1 (R)-phenylethyl)amide; 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid 30 1 -(L-leucine, N-methylamide)amide 9-(l (S)-phenylethyl)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-carboxy- 1,9-nonanedioic acid 1-(L-leucine, N-methylamide)amide 9 -(N-methyl-N-phenyl)amide; WO 00/04892 PCTIUS99/13948 -46 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-carboxy- 1,9-nonanedioic acid 1 -(L-leucine, N-methylamide)amide 9 -(N'-methylpiperazine)amide trifluoroacetic acid salt; 2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid 5 1-(L-leucine, N-methylamide)amide 9-(3-pyridyl)amide; 2(_R)-(2-(4-(1-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid 1-(L leucine, N-methylamide)amide; 2(R)-(2-(4-(1-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-((R)-(S-p methoxybenzyl)penicillamine, N-phenylamide)amide; 10 2(R)-(2-(4-(1 -Propyl)phenyl)ethyl)- 1,5-pentanedioic acid I -((R)-(S-p methoxybenzyl)penicillamine sulfone, N-phenylamide)amide; 2-(2-(4-(1-Propyl)phenyl)ethyl)-4-(I-(4-(2-phthalimido))butyl) 1,5-pentandioic acid 1 -(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-benzoylamino- I -butyl) 15 1,5-pentandioic acid I -(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-pivaloylamino- 1 -butyl) 1,5-pentandioic acid 1 -(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-phenylsulfonylamino- I -butyl) 1,5-pentandioic acid 1 -(L-leucine, N-methylamide)amide; 20 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-(N'-phenylureido)- 1 -butyl) 1 ,5-pentandioic acid 1 -(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-phenyloxycarbonylamino 1 -butyl)- 1,5-pentandioic acid I -(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-N'-benzyloxycarbonylamino-L 25 prolylamino)-1-butyl)-1,5-pentandioic acid 1-(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-cyclopentylamino- I -butyl) 1,5-pentandioic acid I -(L-leucine, N-methylamide)amide; 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-(2-carboxybenzoylamino) I -butyl)- 1,5 -pentandioic acid 1 -(L-leucine, N-methylamide)amide; 30 2(R)-(2-(4-(1 -n-Propyl)phenyl)ethyl)-4-(4-cyano- I -butyl)- 1,5-pentandioic acid I -(L-leucine, N-phenylamide)amide; WO 00/04892 PCT/US99/13948 -47 N-[ 1 (R)-Carboxyethyl]-a-(S)-(9-amino-n-nonyl)]glycine-(L)-leucine, N-phenylamide; N-[ 1 (R)-Carboxyethyl]-a-(S)-(n-octyl)]glycine-(L)-leucine, N-phenylamide; 5 N-[ 1(R)-Carboxyethyl]-x-(S)-(n-octyl)]glycine-(L)-arginine, N-phenylamide; N-[ 1 (R)-Carboxyethyl]-a-(S)-(9-amino-n-nonyl)]glycine-(L)-arginine, N-phenylamide; N-[1 (R)-Carboxyethyl]-ax-(S)-(n-decyl)]glycine-(L)-leucine, 10 N-phenylamide; 1-( 2

-(

4 -Propylphenyl)ethyl)cyclopentane-1,3-dicarboxylic acid 1-(L leucine, N-phenylamide)amide; 1-( 2 -(4-Propylphenyl)ethyl)cyclohexane- 1,3-dicarboxylic acid I -(L leucine, N-phenylamide)amide; 15 N-[1(R)-Carboxyethyl]-c-(S)-2-(4-fluorobiphenyl)-glycyl-(S)-2-(tert butyl)glycine, N-phenylamide; 3 S- [ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]amino- I -methoxy 3,4-dihydrocarbostyril; 3S-[4-(N-Hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl] 20 amino-3,4-dihydrocarbostyril; 3 S-[4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl] amino 1 -methoxy-3,4-dihydrocarbostyril; 3 S-[ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]amino- I -methoxymethyl 3,4-dihydrocarbostyril; 25 1 -Carboxymethyl-3 S-[4-N-hydroxyamino)-2R-isobutyl-3

S

methylsuccinyl]amino-3,4-dihydrocarbostyril; 3 S- [ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]amino I -methoxyethoxymethyl-3,4-dihydrocarbostyril; 3 S-[ 4 -(N-Hydroxyamino)-2R-heptylsuccinyl]amino-1 -methoxy 30 3,4-dihydrocarbostyril; 7-Chloro-3 S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl] amino I -methoxymethyl-3,4-dihydrocarbostyril; WO 00/04892 PCTIUS99/13948 -48 3 S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino- I -methoxyethyl 3,4-dihydrocarbostyril; 3 S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl] amino-i -methoxyethyl 6,7-methylenedioxy-3,4-dihydrocarbostyril; 5 3R-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino- 1 -methoxyethyl 6,7-methylenedioxy-3,4-dihydrocarbostyril; 2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl) (3-morpholin 4-yl-3-oxopropyl)amino]-3-methyl-butyramide; 2-(R)-2-[(2-Benzylcarbamoylethyl)(4-methoxy-benzenesulfonyl) 10 amino]-N-hydroxy-3-methylbutyramide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) (2-[(pyridin-3 ylmethyl)carbamoyl]ethyl)amino)-3-methylbutyramide; 2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl]-[2-(methylpyridin 3-ylmethylcarbamoyl)ethyl]amino)-3-methylbutyramide; 15 4-(3-[1-(R)-1-Hydroxycarbamoyl-2-methylpropyl) (4-methoxybenzenesulfonyl)amino]propionyl)piperazine- 1 -carboxylic acid, tert-butyl ester; 2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3 piperazin- I -ylpropyl)amino)-3-methylbutyramide hydrochloride; 20 2-(R)-2-[(Benzylcarbamoylethyl)(4-methoxy-benzenesulfonyl)amino] N-hydroxy-3-methylbutyramide; 2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl] [(2-morpholin-4 ylethylcarbamoyl)methyl]amino]-3-methylbutyramide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) ([(pyridin-3-ylmethyl) 25 carbamoyl]methyl)amino)-3-methylbutyramide; 2-(R)-3,3,3,-Trifluoro-N-hydroxy-2-[(methoxy-benzenesulfonyl)(3 morpholin-4-yl-3-oxopropyl)amino]propionamide; 2-(R)-N-Hydroxy-2-((4-phenoxybenzenesulfonyl)[2-methylpyridin 4-ylmethylcarbamoyl)ether]amino)-3-methylbutyramide; 30 4-[4-Methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-1 methylpiperidene-4-carboxylic acid hydroxyamide; 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin I-yl)-3 - oxopropyl]amino)-3 -methylbutyramide; WO 00/04892 PCTIUS99/13948 -49 2

-(R)-

2

-[(

2 -Carboxyethyl)(4-methoxybenzene-.sulfonyl)amino]p N-hydroxy-3-methylbutyramide; [(2-Carboxyethyl)(3 , 4 -dimethoxybenzene-sulfonyl)amino] -N-hydroxy acetamide; 5 2

-(R)-

2

-[(

2 -Carbamoylethyl)(4-methoxybenzene-.sulfonyl)amino-N hydroxy-3-methylbutyramide; 2-(R), 3-(R)-3, N-Dihydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3 piperidin- 1 -ylpropyl)amino]-butyramide; 2 -(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) [3-(methylpyridin 10 3 -ylmethylcarbamoyl)propyl]amino)-3 -methylbutyramide; 2 -(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) [2 (methylcarboxymethylcarbamnoyl)ethyl]amino-3 -methyl-butyramide; 2 -(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[( 1 methylpiperidin-4-ylcarbamoyl)methyl]amino).3 -methylbutyramide; 15 2-R--ylhxlNhdoy2-(-ehx-eznsloy) [3 -(4-methylpiperazin- Il-yl)-3 -oxopropyl]amino)-acetamide; 2-(R)-N-Hydroxy-2-[(methoxybenzenesulfonyl)(3 -morpholin-4-yl [3 -oxopropyl)amino]

-

4 -(morpholin-4-yl)butyramide;

[

4 -N-Benzyloxyamino)-2(R)-isobutylsuccinyl] -L-leucyl-L-alanine ethyl 20 ester;

[

4 -N-Benzyloxyamino)-2(R)-isobutylsuccinyl]p3(RS)-aminlarolatam; Na[-NBnyoyrio-()iouysciy]N-N benzyloxycarbonylglycyl)-L-lysyl-L-alanine ethyl ester;

[

4 -(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]yL-eucylglycine ethyl 25 ester;

[

4 -(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]yLleucylglycine isopentylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl] -L-valylglycine ethylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl] -L-leucylglycine 30 ethylamide; Na-[4-(NHydroxyiino)-2(RS)-isobutylsuccinyl]-Ne tert.butoxycarbonyl-L-lysylglycine ethylamide; WO 00/04892 PCT/US99/13948 -50 [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-L tyrosinylglycine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-L tyrosinylglycine ethylamide; 5 [ 4 -(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl ester;

[

4 -(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine isopentyl ester;

[

4 -(N-Hydroxyamino)-2(R)-propylsuccinyl]-L-leucylglycine ethyl ester; 10 [ 4 -(N-Hydroxyamino)-2(RS)-sec.butylsuccinyl]-L-leucylglycine ethyl ester; [4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-leucyl-L-alanine; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine methyl ester; 15 [ 4 -(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylsarconsine ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-proline ethyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-L-alanine 20 isopropyl ester; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2 oxopropylamide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2 methoxyethylamide; 25 [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2,2 dimethoxyethylamide; Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne-glycyl-L-lysine methylamide; Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne 30 (4-carboxybenzoyl)-L-lysl-L-alanine ethyl ester; Na_[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne

(

4 -carboxybenzoyl)-L-lysyl-L-aline; WO 00/04892 PCT/US99/13948 -51 [4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-3(RS)-aminooctahydro 2H-azonin-2-one; [4-(N-Hydroxyamino)-3(S)-methyl-2(R)-isobutyl-succinyl]-L leucylglycine ethyl ester; 5 [(3-Aminophthalimido)methyl][(RS)-4-methyl-2-[[(S)3-methyl-1 (methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid; [(RS)-4-Methyl-2-[[(S)-3-methyl-1-(methyl-carbamoyl)butyl] carbamoyl]pentyl](1,8-naphthalenedi-carboximidomethyl)phosphinic acid; [(R or S)-4-Methyl-2-[[(R or S)- 2 -oxo-3-azacyclotridecyl] 10 carbamoyl]pentyl](1.8-naphthalenedicarboximidomethyl)phosphinic acid; N-[N-[(R or S)-2[[[[[N-[1-(Benzyloxy)carbonyl]-L-prolyl]-L leucyl]amino]methyl]hydroxyphosphinyl]-methyl]-4-methylvaleryl]-L leucyl]-L-alanine; [[1,4-Dihydro-2,4-dioxo-3(2H)-quinazolinyl]-methyl][[(R or S)-4 15 methyl-2-[[(R or S)- 2 -oxo-3-azacyclotridecyl]carbamoyl]pentyl]phosphinic acid;

N

2 -[(R)-Hydroxycarbamoylmethyl]-4-methylvaleryl]-N I,3 dimethyl-L-valinainide;

N

2 -[2(R or S)-[[[(5-Bromo-2,3-dihydro-6-hydroxy)-1,3-dioxo-1H benz[d,e]isoquinol-2-yl)methyl]-[(hydroxy)phosphinyl]methyl]-4-methylvaleryl] 20 N 1,3-dimethyl-L-valinamide;

N

2 -[(R or S)-[[(R)-(Amino)[(5-bromo-2,3-dihydro-6-hydroxy-1,3-dioxo 1H-benz[d,e]isoquinol-2-yl)methyl](hydroxy)phosphinyl]methyl]-4 methylvaleryl]-N 3 , 1 -dimethyl-L-valinamide hydrobromide;

N

2 -[2(R or S)-[1(S)-(Hydroxycarbamoyl)ethyl-4-methylvaleryl] 25 N ,3-dimethylvalinamide;

N

2 -[2(R)-[ 1 (R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4 methylvaleryl]-NI,3-dimethyl-L-valinamide;

N

2 -[2(R)-[ I (R or S)-(Hydroxycarbamoyl)-4-(methoxy carbonyl)butyl]-4-methylvaleryl]-N I,3-dimethyl-L-valinamide; 30 M 2 -[2(R)-[ I (R or S)-(Hydroxycarbamoyl)-4-phenyl-butyl] 4-methylvaleryl]-N 1 ,3-dimethyl-L-valinamide; WO 00/04892 PCT/US99/13948 -52

N

2 -[2(R)-[1 (R or S)-(Hydroxycarbamoyl)-2-succinimidoethyl]-4 methylvaleryl]-NI ,3-dimethyl-L-valinamide; 4-[2(R)-[i(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4 methylvaleryl]morpholine; 5 4-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4 methylvaleryl]tetrahydro- 1,4-thiazine; 1-[2(R)-[I(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4 methylvaleryl]-4-piperidinol; 1-[2(R)-[ I (R or S)-(Hydroxycarbamoyl)-2-(1,2-dimethyl-3,5 10 dioxo-1,2,4-triazolidin-4-yl)ethyl]-4-methylvaleryl]piperidine; 4-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(3-methyl-2,5-dioxo 1 -imidazolidinyl)ethyl]-4-methylvaleryl]tetrahydro- 1,4-thiazine; Hexahydro-2-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl] 4-methylvaleryl]-N-methyl-3(S)-pyridazinecarboxamide; 15 1-[2(R)-(R or S)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5 dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol; [4-(N-Hydroxyamino)-2(R or S)-heptylsuccinyl]-L-leucyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(R or S)-nonylsuccinyl]-L-leucyl-L-leucine 20 ethylamide; [4-(N-Hydroxyamino)-2(R or S)-heptyl-3(S)-methylsuccinyl]-L leucyl-L-leucine ethylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-(phthalimidomethyl) succinyl]-L-leucyl-L-leucine ethylamide; 25 [ 4 -(N-Hydroxyamino)-2(RS)-nonylsuccinyl]-L-tert.butylglycine methylamide;

[

4 -(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-phenylalanine methylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-phthalimidomethyl) 30 succinyl]-L-tert.butylglycine methylamide; [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-(3-phenylpropyl)-succinyl] L-leucyl-L-leucine ethylamide; WO 00/04892 PCTIUS99/13948 -53 [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-leucine methylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-leucine neopentylamide;

[

4 -(N-Hydroxyamino)-2(RS)-heptylsuccinylyLalanyl.L-leucine ethylamide; 5 [4-(N-Hydroxyamino)-2(RS)-heptylsucciny]LNe-phthaloyl)> lysyl-L-leucine ethylamide;

[

4 -(N-Hydroxyamino)-2(RS)-undecylsuccinyl-LeucylLleucine ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-phenylalanyl-L-leucine 10 ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-nonalyl-L-leucine ethylamide;

[

4 -(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -phenylalanine tert.butylamide; 15 [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-tert.butylglycine methylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-neopentylglycine methylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-homophenylalanyl-L 20 leucine ethylamide; [4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl] -L-cyclohexylalanine methylamide; [4-(N-Hydroxyamino)-2(RS)-isooctylsuccinyl] -L-phenylalanine methylamide; 25 [ 4 -(N-Hydroxyamino)-2(R)-heptylsucciny]-L-neonpentylglycine methylamide; [4-(N-Hydroxyamino)-2(R)-heptylsuccinyl] -(D or ) f34-dimethylphenylalanine methylamide; [4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-(D or L)-threo 30 f-methylphenylalanine methylamide;

[

4 -(N-Hydroxyamino)-2(R)-heptylsuccinyl]pDL-erthro. f-methylphenylalanine methylamide; WO 00/04892 PCT/US99/13948 -54 [4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-[(3-methyl-2,5-dioxo 1-imidazolidinyl)methyl]succinyl]-L-leucyl-L-leucine ethylamide;

N

2 -[3-Cyclobutyl-2(R or S)-[(hydroxycarbamoyl)-methyl]-propionyl] N 1,3-dimethyl-L-valinamide; 5 N 2 -[3-Cyclopropyl-2(R or S)-[(hydroxycarbamoyl)-methyl] propionyl]-NI,3-dimethyl-L-valinamide;

N

2 -[3-Cyclopentyl-2(R or S)-[(hydroxycarbamoyl)-methyl] propionyl]-NI,3-dimethyl-L-valinamide;

N

2 -[3 -Cyclopropyl-2(R)- [1 (R or S)- [(hydroxy-carbamoyl)-2-(3,4,4 10 trimethyl-2,5-dioxo- 1 -imidazolidinyl)ethyl]propionyl]-N 1 ,3-dimethyl L-valinamide;

N

2 -[3-Cyclopropyl-2(R)-[l(R or S)-[(hydroxy-carbamoyl) 4-phenylbutyl)]propionyl]-NI,3-dimethyl-L-valinamide;

N

2 -[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxy-carbamoyl) 15 4-phenylbutyl]propionyl]-N 1 ,3-dimethyl-L-valinamide;

N

2 -[3-Cyclopentyl-2(R)-[ I (R or S)-(hydroxycarbamoyl) 4-phenylbutyl]propionyl]-NI,3-dimethyl-L-valinamide; 1-[3-Cyclopropyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo- 1 -imidazolidinyl)ethyl]propionyl]piperidine; 20 1-[3-Cyclopropyl-2(R)-[l(R or S)-(hydroxy-carbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]-4-piperidinol; 1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]piperidine; 1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4 25 trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol; 1-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol; 1-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]piperidine; 30 3-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl 2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo [3.2.2]nonane; WO 00/04892 PCT/US99/13948 -55 3- [3-Cyclopropyl-2(R)-[ 1(R or S)-(hydroxy-carbamnoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo-l1-imidazolidinyl)ethyl]propionyl] -3 -azabicyclo [3.2 .2]nonane; 3 -[3-Cyclopentyl-2(R)-[ 1(R or S)-(hydroxy-carbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo-lI-imidazolidinyl)ethyl]propionyl]-3 -azabicyclo [3 .2.2]nonane; 5 1- [3-Cyclohexyl-2(R)- [1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- 1 -imidazolidinyl)ethyl]propionyl]piperidine; 4- [3-Cyclopentyl-2(R)-[ 1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- 1 -imidazolidinyl)ethyl]propionyl]tetrahydro- 1 ,4-thiazine; 4-[3 -Cyclopentyl-2(R)- [1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 10 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]tetrahydro- I,4-thiazine S,S-dioxide; 4- [3-Cyclobutyl-2(R)- [1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- 1 -imidazolidinyl)ethyl]propionyl]tetrahydro- 1 ,4-thiazine; 3- [3-Cyclopentyl-2(R)-[ 1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 15 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]-5,-dimethyl-Npropyl [4(R)-thiazolidinecarboxamide; 4- [3-Cyclopentyl-2(R)-[ 1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- 1 -imidazolidinyl)ethyl]propionyl]morpholine; 3 -[3 -Cyclopentyl-2(R)- [1(R or S)-(hydroxy-carbamoyl)-2-(3 ,4,4 20 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl] -N,5 ,5-trimethyl-4(R) thiazolidinecarboxamide; 4- [3 -Cyclobutyl-2(R)- [1I (R or S)-(hydroxy-carbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine; 4- [3-Cyclobutyl-2(R)-[ 1(R or S)-(hydroxy-carbamoyl)-2-(3 ,4,4 25 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]morpholine; 1- [3 -Cyclobutyl-2(R)- [1 (R or S)-(hydroxy-carbamnoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]pyrrohidine; 8- [3-Cyclobutyl-2(R)-[ 1(R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- I-imidazolidinyl)ethyl]propionyl] -1 ,4-dioxa-8 30 azaspiro[4,5]decane; 1 -[3 -Cyclobutyl-2(R)-[ I (R or S)-(hydroxycarbamoyl)-2-(3 ,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl] -4-methoxypiperidine; WO 00/04892 PCT/US99/13948 -56 1- [3 -Cyclobutyl-2(R)- [1 (R or S)-(hydroxycarbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]octahydroazocine; 1-[3-Cyclobutyl-2(R)-[I(R or S)-(hydroxycarbamoyl)-2-(5,5 dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine; 5 1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4 trimethyl-2,5-dioxo- I -imidazolidinyl)ethyl]propionyl]hexahydroazepine; 1-[3-Cyclobutyl-2(R)-[2-(hexahydro- 1,3-dioxo-pyrazolo[1,2-a] [1,2,4] triazol-2-yl)- I (R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine; 1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2 10 phthalimidoethyl]propionyl]piperidine; 2- [2(R)-[1 (R or S)-(Hydroxycarbamoyl)-4-phenylbutyl]nonanoyl] hexahydro-N-methyl-3(S)-pyridazinecarboxamide; N-Cyclohexyl-hexahydro-2-[2(R)-[ 1 (RS)-(hydroxycarbamoyl)-4 phenylbutyl]nonanoyl]-3(S)-pyridazinecarboxamide; 15 Hexahydro-2- [2(R)-[ 1 (RS)-(hydroxycarbamoyl)-4-phenylbutyl]nonanoyl] N-(2,2,6,6-tetramethyl-4-piperidinyl)-3 (S)-pyridazinecarboxamide; 1-[2(R)-[1(R or S)-Hydroxycarbamoyl)-4-phenylbutyl]nonanoyl] piperidine;

N

2 -[2(R)-[1(RS)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 20 imidazolidinyl)ethyl]nonanoyl]-N1-methyl-L-prolinamide; 1-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 imidazolidinyl)ethyl]nonanoyl]piperidine; Hexahydro-2-[2(R)-i (R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5 dioxo-1-imidazolidinyl)ethyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide; 25 Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)-3-phenylpropyl] undecanoyl]-N-methyl-3(S)-pyridazinecarboxamide; Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)-3-phenylpropyl] undecanoyl]-N-methoxy-N-methyl-3(S)-pyridazinecarboxamide; Hexahydro-2-[2(R or S)-[(1(S)-(hydroxycarbamoyl)-3-phenylpropyl] 30 undecanoyl]-N-(1, 2 ,2,6,6-pentamethyl-4-piperidinyl)-3(S) pyridazinecarboxamide; WO 00/04892 PCT/US99/13948 -57 Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)ethyl]undecanoyl]-N methyl-3(S)-pyridazinecarboxamide; Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)-3-phenylpropyl] nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide; 5 Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)ethyl]nonanoyl]-N methyl-3(S)-pyridazinecarboxamide; 1-[2(R or S)-[l(S)-(Hydroxycarbamoyl)ethyl]undecanoyl]piperidine; 1-[2-(R or S)-[1(S)-(Hydroxycarbamoyl)-3-phenylpropyl]undecanoyl] piperidine; 10 Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)-3-phenylpropyl] undecanoyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide; Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)ethyl]undecanoyl]-N (2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide; 1-[2(R or S)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]undecanoyl] 15 piperidine; 4-[2(R or S)-[1 (S)-(hydroxycarbamoyl)-4-phenylbutyl]undecanoyl] morpholine; I -(Benzyloxycarbonyl)-hexahydro-2- [2(R)- [(R or S)-(hydroxycarbamoyl) 4-phenylbutyl]nonanoyl]-N-(cx(S)-methylbenzyl)-3(S)-pyridazinecarboxamide; 20 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-(carboxy)pentanoyl] L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6 (phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]- 6 -(propylamino) 25 6 -(oxo)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-(6RS)-6 (hydroxy)heptanoyl]-L-phenylalanine N-methylamide; (2S)-N-2-[(2'R)-2'-[ 2 "-(Hydroxyamino)-2"-(oxo)ethyl]-6' (hydroxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; 30 (2S)-N-2-[(2'R)-2'-[ 2 '-(Hydroxyamino)-2"-(oxo)ethyl]-6' (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; WO 00/04892 PCTIUS99/13948 -58 N-[(2'R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(4' oxobutylamino)hexanoyl]-L-phenylalanine N-methylamide; 2(S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6' (propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; 5 N-[(2R)-2-[(I'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6 (phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[(I'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6 (oxo)-6-(propylamino)hexanoyl]-L-phenylalanine N-methylamide; (2S)-N-2[(2'R)-[(I"R)-1"-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2 10 yl)methyl-2"-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl] amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6 (propylamino)hexanoyl]-L-phenylalanine N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(1"S)-1"-(Methyl)-2"-(hydroxyamino)-2" 15 (oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(1"S)-1"-(Methyl)-2"-(hyroxyamino)-2" (oxo)ethyl]- 6 '-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-phenylethylamide; 20 (2S)-N-2-[(2'R)-2'-[(1"S)-1"-(Methyl)-2"-(hydroxyamino)-2" (oxo)ethyl]- 6 '-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide;

(

2 S)-N-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' (phenylmethoxy)hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4' 25 sulfamoyl)phenylethylamide; N-[2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6'-(phenylmethoxy) hexanoyl]-L-(3,5-dimethyl)phenylalanine

N-

2

-(

4 '-sulfamoyl)phenylethylamide; (2S)-N-2'-[( 2

'R)-

2

'-[

2 "-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4 methoxy)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4' 30 sulfamoyl)phenylethylamide; WO 00/04892 PCT/US99/13948 -59 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' [(4-methyl)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide; (2S)-N-2'-[( 2 'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' 5 [(1 -oxo)butylamino]hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)phenylethylamide; (2S)-N-2-[(2'R)-2'-[(l"S)-1"-(Methyl)-2"-(hydroxyamino)-2" (oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; 10 (2S)-N-2-[(2'R)-2'-[(1"S)-1"-( 2 -Methylpropyl)-2"-(hydroxyamino) 2"-(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;

N-[(

2

R)-

2

-[

2 '-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenoxy)hexanoyl]-L phenylalanine N-methylamide; 15 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenoxy)heptanoyl]-L phenylalanine N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2 phenylethylamide; 20 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4' sulfamoyl)phenylethylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-(phenylmethoxy) pentanoyl]-L-phenylalanine N-methylamide; 25 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenylmethoxy) heptanoyl]-L-phenylalanine N-methylamide;

N-[(

2 R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenyloxy)hexanoyl] L-phenylalanine N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl] 30 L-phenylalanine N-methylamide; WO 00/04892 PCT/US99/13948 -60 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(2 phenethylamino)-6'-(oxo)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' 5 [(4-methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' [(4-chlorophenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' [(3-methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; 10 ( 2

S)-N-

2

'-[(

2 'R)-2'-(carboxymethyl)-6'-(3-methylphenoxy)hexanoyl] amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[ 2 '-(Hydroxyamino)-2'-(oxo)ethyl]-5-(carboxy)pentanoyl] L-phenylalanine N-methylamide; N-[(2R)-2-[ 2 '-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenylmethoxy) 15 hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[ 2 '-(Hydroxyamino)-2'-(oxo)ethyl]-6-(propylamino)-6 (oxo)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[ 2 '-(Hydroxyamino)-2'-(oxo)ethyl]-(6RS)-6-(hydroxy) heptanoyl]-L-phenylalanine N-methylamide; 20 (2S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' (hydroxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; (2S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2'R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(4' 25 oxobutylamino)hexanoyl]-L-phenylalanine N-methylamide; 2(S)-N-2-[(2'R)-2'-[ 2 "-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6' (propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[(1'S)- I '-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl] 6-(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide; 30 N-[(2R)-2-[(1'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl] 6 -(oxo)- 6 -(propylamino)hexanoyl]-L-phenylalanine N-methylamide; WO 00/04892 PCT/US99/13948 -61 (2S)-N-2[(2'R)-[(l "R)- 1 "-(1,3-dihydro- 1,3-dioxo-2H-isoindol-2 yl)methyl- 2 "-(hydroxyamino)-2"-(oxo)ethyl]-6'-(phenylmethoxy)hexanoyl] amino-3,3-dimethylbutanoic acid N-methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6 5 (propylamino)hexanoyl]-L-phenylalanine N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(I"S)-1"-(Methyl)-2"-(hydroxyamino)-2" (oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(I"S)-1"-(Methyl)-2"-(hydroxyamino)-2" 10 (oxo)ethyl]- 6 '-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-phenylethylamide; (2S)-N-2-[(2'R)-2'-[(1"S)-1"-(Methyl)-2"-(hydroxyamino)-2" (oxo)ethyl]- 6 '-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide; 15 (2S)-N-[( 2 'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' (phenylmethoxy)hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4' sulfamoyl)phenylethylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6'-(phenylmethoxy) hexanoyl]-L-(3,5-dimethyl)phenylalanine

N-

2

-(

4 '-sulfamoyl)phenylethylamide; 20 (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4 methoxy)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4' sulfamoyl)phenylethylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"'-(oxo)ethyl]-6'-[(4 methyl)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4' 25 sulfamoyl)phenylethylamide; (2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(1 oxo)butylamino]hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4' sulfamoyl)phenylethylamide; (2S)-N-2-[(2'R)-2'-[(I"S)-1"-(Methyl)-2"-(hydroxyamino)-2" 30 (oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; WO 00/04892 PCT/US99/13948 -62 (2S)-N-2-[(2'R)-2'- [(1 "S)- I "-( 2 -Methylpropyl)-2"-(hydroxyamino) 2"*-(oxo)ethyl] -6-(phenylmethoxy)hexanoyl]amino-3 ,3 -dimethylbutanoic acid N-methylamide; N-[(2R)-2- [ 2 '-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenoxy)hexanoyl] 5 L-phenylalanine N-methylamide; N- [(2R)-2- [2'-(Hydroxyamino)-2'-(oxo)ethyl] -7-(phenoxy)heptanoyl] -L phenylalanine N-methylamide; (2S)-N-2'-[(2'R)-2'-[2*"-(Hydroxyamino)-2"-(oxo)ethyl] -6' (phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid 10 N-2-phenylethylamide; (2 S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"4-oxo)ethyl] -6' (phenylmethoxy)hexanoyl]amino-3 ,3 -dimethylbutanoic acid N-2-(4' sulfamoyl)phenylethylamide; N- [(2R)-2- [2'-(Hydroxyamino)-2'-(oxo)ethyl]-5 15 (phenylmethoxy)pentanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2- [2'-(Hydroxyamino)-2'-(oxo)ethyl] 7-(phenylmethoxy)heptanoyl] -L-phenylalanine N-methylamide; N- [(2R)-2- [2'-(Hydroxyamino)-2'-(oxo)ethyl] -6 (phenyloxy)hexanoyl]-L-phenylelanine N-methylamide; 20 N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]y7 [(phenyloxy)heptanoyl] -L-phenylalanine N-methylamide; (2 S)-N-2'- [( 2 'R)-2'-[2"'-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(2 phenethylamino)-6'-(oxo)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; 25 (2 S)-N-2'- [( 2 'R)-2'-[2"'-(Hydroxyamino)-2"-(oxo)ethyl]..6' [(4 methylphenoxy)hexanoyl]amino-3 ,3-dimethylbutanoic acid N-methylamide;

(

2 S)-N-2'-[(2'R)-2'-[2"-(Hydroxyan-ino)-2"-(oxo)ethyl] -6'- [(4 chlorophenoxy)hexanoyl]amino-3 ,3-dimethylbutanoic acid N-methylamide; (2S)-N-2'- [(2'R)-2'- [2"-(Hydroxyamino)-2"-(oxo)ethyl]p6' [(3 30 methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide; WO 00/04892 PCT/US99/13948 -63 (2S)-N-2'- [( 2

'R)-

2 1 -(Carboxymethyl)-6'-(3-methylphenoxy)hexanoyl] amino-3 ,3-dimethylbutanoic acid N-methylamide; (3R, 1 OS)-5-Methyl-3-(9-oxo- 1,8-diazatricyclo[ 10.6.1 .O]nonadeca 12(19), 13(18), 14,1 6-tetraen- I 0-ylcarbamoyl)hexanoic acid; 5 (3R, I OS)-N-Hydroxy-5-methyl-3-(9-oxo- 1,8-diazatricyclo[ 10.6. 1.0] nonadeca- 12(19), 13(18), 14,1 6-tetraen- 10-ylcarbamnoyl)hexanamide; (3R, 11 S)-N-Hydroxy-5-methyl-3 -(1 0-oxo-I,9-diazatricyclo[ 11.6. 1.0] eieosa- 13 (20), 14(19), 15,1 7-tetraen- 11I -ylcarbamoyl)hexanamide; (3R,9S')-5-Methyl-3 -(8-oxo- 1 ,7-diazatricyclo [9.6.1 .0]octadeca 10 11(1 8), 12(17), 13,1 5-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-N-Hydroxy-5-methyl-3 -(8-oxo- 1 ,7-diazatricyclo [9.6.1.0] octadeca 11I(1 8), 12(17), 13,1 5-tetraen-9-ylcarbamoyl)hexanamide; (1 OS)-[4-Methyl-2-(9-oxo- 1 ,8-diazatricyclo[ 10.6.1 .0]nonadeca 12(19), 13(18), 14,1 6-tetraen- I 0-ylcarbamoyl)pentyl] -(quinolin-2 15 ylthiomethyl)phosphinic acid; (3R, I OS)-N-Hydroxy-5-methyl-2-methoxycarbonyl3(9-oxo. 1,8 diazatricyclo[ 10.6..1 .0]nonadeca- 12(19), 13(18), 14,1 6-tetraen- 1 0-ylcarbamoyl) hexanamide; N-(4-Methy1-2-carboxymethylpentanoy1>-L-eucine-N'. 20 ( 4 -methoxycarbonylphenyl)carboxamide;

N-(

4 -Methyl-2-(N"T hydroxycarbamoyl)methylpentanoyl>L-leucine N'-(4-methoxycarbonylphenyl)carboxamide; N-(4-Methyl-2-(N" "hydroxycarbamoyl)methylpentanoyl>L-eucine-N ' (4-carboxyphenyl)carboxamide; 25 N-( 4 -Methyl-2-(N"- hydroxycarbamoyl)methylpentanoyl)-L tryptophan-N'L(4-carboxyphenyl)carboxamide; N-(4-Methyl-2-(N"-Lhydroxycarbamoyl)methylpentanoyl)> L-ylhxllcn-'(-ehoyabnlhnlcroaie N-(4-Methyl-2-(N "-hydroxycarbamoyl)methylpentanoyl>Lt-eucine-N'. 30 ( 4 -methoxycarbonylphenyl)carboxamide; (3R, I 0S)-6-Biphenyl-4-yl)-3-(9-oxo- I ,8-diazatricyclo[ 10.6.1 .0]onadeca 12(19), 13(18), 14,1 6-tetraen-1I0-ylcarbamoyl)hexanoic acid; WO 00/04892 PCT/US99/13948 -64 (3R, 1 OS)-3-(9-Oxo- 1,8-diazatricyclo[ 10.6.1 .0]nonadeca 12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-5-(thiophen-2-yl)pentanoic acid; (3R, I OS)-3-Cyclopentyl-3-(9-oxo- 1,8-diazatricyclo[ 10.6.1 .0]nonadeca 12(19),13(18),14,16-tetraen-10-ylcarbamoyl)propionic acid; 5 (3R,IOS)-4-Cyclopentyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca 12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; (3R,10S)-4-Cyclopropyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca 12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; (3R,1OS)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0]nonadeca 10 12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; (3R,I0S)-N-Hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0] nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; (3R, 11S)-N-Hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[ 11.6.1.0] eicosa- 13(20),14(19),15,17-tetraen- 11 -ylcarbamoyl)hexanamide; 15 (3R,9S)-N-5-Methyl-3-(8-oxo- 1,7-diazatricyclo[9.6.1.0]octadeca 11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-N-Hydroxy-5-methyl-3-(8-oxo- 1,7-diazatricyclo[9.6.1 .0]octadeca 11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; (1 OS)-2-Mercaptomethyl-4-methyl-N-(9-oxo- 1,8-diazatricyclo[ 10.6.1.0] 20 nonadeca- 12(19),13(18),14,16-tetraen- I 0-ylcarbamoyl)pentanamide; (1 OS)-2-Acetylthiomethyl-4-methyl-N-(9-oxo- 1,8-diazatricyclo[ 10.6.1.0] nonadeca- 12(19),13(18),14,16-tetraen- 1 0-ylcarbamoyl)pentanamide; (3R, 10S)-2-(Methanesulfonamidomethyl)-5-methyl-3-(9-oxo- 1,8 diazatricyclo[ 10.6.1 .0]nonadeca- 12(19),13(18),14,16-tetraen- I 0-ylcarbamoyl) 25 hexanoic acid; (3R, 1OS)-2-(3-Ethylureidomethyl)-5-methyl-3-(9-oxo- 1,8 diazatricyclo[ 10.6.1 .0]nonadeca- 12(19),13(18),14,16-tetraen- 10 ylcarbamoyl)hexanoic acid; (3R,9S)-N-Hydroxy-2-hydroxy-5-methyl-3-(8-oxo- 1,7 30 diazatricyclo[9.6. I.0]octadeca- 11(18),12(17),14,16-tetraen-9 ylcarbamoyl)hexanamide or its (2S,3R,9S) stereoisomer; WO 00/04892 PCT/US99/13948 -65 (3R, 1 OS)-N-Hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo- 1,8 diazatricyclo[ 10.6.1.0]nonadeca-12(19),13(18),14,16-tetraen- I 0-ylcarbamoyl) hexanamide; (3R,9S)-5-Methyl-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0]octadeca 5 11 (18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-Cyclobutylmethyl-N-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)succinamic acid; (3R,9S)-3-(8-Oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0]octadeca 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid; 10 (3R,9S)-5-(4-Chlorophenoxy)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid; (3R,9S)-5-(4-Chlorophenoxy)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid ethyl ester; (3R,9S)-3-(8-Oxo- 1,7-diazatricyclo[9.6.1 .0]octadeca- 11(18),12,14,16 15 tetraen-9-ylcarbamoyl)pentanoic acid ethyl ester; (3R,9S)-6-(4-Hydroxy-phenyl)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa- 1,7-diazatricyclo[9.6.1 .0]octadeca 1 1(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic acid; 20 (3R,9S)-6-[4-(3-Hydroxy-propoxy)-phenyl]-3-( 8 -oxo-4-oxa 1,7-diazatricyclo[9.6.1.0]octadeca- 11(18),12,14,16-tetraen 9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa- 1,7-diazatricyclo[9.6.1 .0]octadeca 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-5-(4-phenoxy-phenyl)pentanoic acid; 25 (3R,9S)-6-[4-(2-Hydroxy-ethoxy)-phenyl]-3-( 8 -oxo-4-oxa 1,7-diazatricyclo[9.6. I.O]octadeca- 11(18),12,14,16-tetraen 9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-6-[4-(2-pyrrolidin-1-yl 30 ethoxyphenyl]hexanoic acid; (3R,9S)-6-(4-Methoxy-phenyl)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; WO 00/04892 PCTIUS99/13948 -66 (3R,9S)-6-[4-(2-Methoxy-ethoxy)-phenyl]-3-(8-oxo-4-oxa 1,7-diazatricyclo[9.6. 1.0]octadeca- 11(18),12,14,16-tetraen 9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca 5 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-5-phenyl-pentanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1 .0]octadeca 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-6-phenyl-hexanoic acid; (3R,9S)-6-(3-Hydroxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)hexanoic acid; 10 (3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1 .0]octadeca 11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-[4-(3-piperidin-1-yl propoxy)phenyl]hexanoic acid; (3R,9S)-6-[4-(3-Dimethylamino-propoxy)-phenyl]-3-(8-oxo-4-oxa 1,7-diazatricyclo[9.6.1.0]octadeca-1 1(1 8 ),1 2 ,14,16-tetraen 15 9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-[ 4 -(2-Dimethylamino-ethoxy)-phenyl]- 3 -(8-oxo-4-oxa 1,7-diazatricyclo[9.6. 1.0]octadeca- 11(18),12,14,16-tetraen 9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-(4-Cyano-phenyl)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] 20 octadeca- 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-Naphthalen-2-yl-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6.1.0] octadeca- 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)hexanoic acid; (3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)-6-(4-pyrrol- I -yl)hexanoic acid; 25 (3R,9S)-6-(4-Hydroxy-3-methyl-phenyl)-3-(8-oxo-4-oxa 1,7-diazatricyclo[9.6. I.0]octadeca- 11(18),12,14,16-tetraen 9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-(4-Benzyloxy-phenyl)-3-(8-oxo-4-oxa 1,7-diazatricyclo[9.6. I.0]octadeca- 11(18),12,14,16-tetraen 30 9-ylcarbamoyl)hexanoic acid; (3R,9S)-6-[4-(4-Aminobutoxy-phenyl)]-3-( 8 -oxo-4-oxa 1,7-diazatricyclo[9.6. 1.0]octadeca-1 1(1 8 ),1 2 ,14,16-tetraen 9-ylcarbamoyl)hexanoic acid; WO 00/04892 PCT/US99/13948 -67 (3R,9S)-5-(4-Methoxy-phenyl)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6. 1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid; (3R,9S)-6-(4-Amino-phenyl)-3-(8-oxo-4-oxa- 1,7-diazatricyclo[9.6. 1.0] octadeca- 11(18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid; 5 (3R,9S)-3-(8-Oxo-4-oxa- 1,7-diazatricyclo[9.6.1 .0]octadeca 11(18),12,14,1 6 -tetraen- 9 -ylcarbamoyl)-6-[4-(pyridin-4-ylmethoxy)phenyl] hexanoic acid; (3R,9S)-6-(4-Acetylamino-phenyl)-3-(8-oxo-4-oxa-1,7 diazatricyclo[9.6.1.0]octadeca- 11(18),12,14,1 6 -tetraen-9-ylcarbamoyl)hexanoic 10 acid; Na-[[ 3 -(N-Hydroxycarbamoyl)-4-methylthio-2-propoxymethyl]butylyl] N,O-dimethyltyrosine amide; Nu- [[3-(N-Hydroxycarbamoyl)-4-isopropylthio-2-propoxymethyl] butylyl]-N,O-dimethyltyrosine amide; 15 Na-[[3-(N-Hydroxycarbamoyl)-2-propylthio]butylyl]-N,0 dimethyltyrosine amide; N-[N-(1 -Phosphono-3-phenylpropyl)-(S)-leucyl]-(S)-phenylalanine-N methylamide; N-[N-(I-Phosphono-3-(4-bromo-1,8-naphthalene-dicarboximido)propyl) 20 (S)-leucyl]-(S)-phenylalanine methylamide; N-[N-(1 -Phosphono-3-(benzyloxycarbonylamino)propyl)-(S)-leucyl]-(S) phenylalanine methylamide; N-[N-(1 -Phosphono-3-(2-hydroxyphenyl)propyl)-(S)-leucyl]-(S) phenylalanine methylamide; 25 N-[N-(1 -Phosphono-3-(methylmercapto)propyl)-(S)-leucyl]-(S) phenylalanine-N-methylamide; N-[N-(1 -Phosphono-3 -(methylsulphinyl)propyl)-(S)-leucyl]-(S) phenylalanine-N-methylamide; N-[N-(1 -Phosphono-3-(methylsulphonyl)propyl)-(S)-leucyl]-(S) 30 phenylalanine-N-methylamide; N-[N-(1 -Phosphono-3-(1, 8 -naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-tryptophan-N-methylamide; WO 00/04892 PCTIUS99/13948 -68 N-[N-(1 -Phosphono-3-(1,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-lysine-N-methylamide; N-[N-(1 -Phosphono-3-(1, 8 -naphthalenedicarboximido)propyl)-(S)-leucyl] (-)-aminoazacyclotridecan-2-one; 5 N-[N-(1 -Phosphono-3-(1,8-naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-lysine-N-(aminoethyl)amide; N-[N-(1 -Phosphono-3-(1, 8 -naphthalenedicarboximido)propyl)-(S)-leucyl] (S)-lysine-N-(ethylpyrrolidine)amide; N-[N-(1 -Phosphono-3-(1, 8 -naphthalenedicarboximido)propyl)-(S)-leucyl] 10 (S)-lysine-N-(ethyl-N-methylpiperazine)amide; N-[N-(1 -Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S) leucyl]-(S)-phenylalanine-N-methylamide; and N-[N-(1 -Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S) leucyl]-(S)-lysine-N-methylamide. 15 As noted above, numerous inhibitors of matrix metalloproteinases are known. A large number of inhibitors are characterized as hydroxamic acid-based and/or carboxylic acid-based compounds. Typical of such compounds are those described in the following references, all of which are incorporated herein by reference, since all of the disclosed compounds can be used in the method of this 20 invention. US 4,599,361 (Searle) US 4,771,038 (ICI) US 4,996,358 (Roche) US 4,918,105 (Bellon) 25 US 5,304,604; US 5,514,677 (British Biotechnology) US 5,240,958; US 5,310,763; US 5,530,161 (British Biotechnology) US 5,453,438 (British Biotechnology) US 5,239,078 (Glycomed) US 5,183,900 (Glycomed) 30 US 5,270,326 (Glycomed) WO 92/17460 (Smith-Kline Beecham) US 5,300,501 (Celltech) US 5,304,549 (Roche) WO 00/04892 PCT/US99/13948 -69 US 5,256,657 (Sterling Winthrop) US 5,300,674; US 5,412,145 (British Biotechnology) US 5,387,610; US 5,616,605 (Research Corporation Technologies) US 5,442,110; US 5,473,100 (Yamanouchi) 5 US 5,643,908 (Sankyo) US 5,525,629 (British Biotechnology) US 5,569,665 (Celltech) US 5,530,128 (Celltech) US 5,318,964; US 5,447,929 (Roche) 10 US 5,643,964; US 5,700,838 (British Biotechnology) WO 97/27174 (Shionogi) An especially preferred group of compounds to be employed in the present method are those described in WO 95/35275 and WO 95/35276, both of which are incorporated herein by reference. Typical compounds from within these groups to 15 be employed include: N-Hydroxy- 2

-[[(

2

-(

4 -methoxy-phenoxy)-ethyl-(toluene-4-sulfonyl) amino]-acetamide; N-Hydroxy-2-[( 4 -phenoxy-ethyl)-toluene-4-sulfonyl) amino]-acetamide; N-Hydroxy- 2 -[(4-methoxy-benzenesulfonyl)-nonyl-amino]-acetamide; 20 2 -[-Decyl-(toluene- 4 -sulfonyl)-amino]-N-hydroxy-acetamide; 2-Benzyl-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide; N-Hydroxy-2-[(2-methoxy-benzyl)-(octane-1-sulfonyl)-amino]-acetamide; 2-[(2-Ethoxy-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide; N-Hydroxy-2-[(naphthalen-2-yl-methyl)-(octane-1 -sulfonyl)-amino] 25 acetamide; 2-[(4-Chloro-benzyl)-(octane- I -sulfonyl)-amino]-N-hydroxy-acetamide, and salts, solvates, or hydrates thereof. Another class of matrix metalloproteinase inhibitors are aryl sulfonamides of the formula WO 00/04892 PCTIUS99/13948 -70 o RIO || 1 11 Ar- S-N-C-C- NHOH o CH 2 R R2 where Ar is carbocyclic or heterocyclic aryl, and R, R I, and R 2 include hydrogen, alkyl, aryl, heteroaryl, amino, substituted and disubstituted amino. These compounds are disclosed in European Patent Number 0606046, incorporated 5 herein by reference. Specific compounds to be employed in the present method include: N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl) amino] acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclo-hexylmethyl)amino] acetamide; 10 N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclo-hexyl)amino] acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](phenethyl)amino]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-methylbutyl)amino] acetamide; 15 N-Hydroxy-2-[[4-methoxybenzenesulfonyl](sec-butyl)amino]acetamide; N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl](tert-butyl)amino]acetamide; N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl](4-fluorobenzyl)amino] acetamide; N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl](4-chlorobenzyl)amino] 20 acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isopropyl)-amino]acetamide; N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl](4-methylbenzyl)amino] acetamide; 4 -N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl) 25 amino]- 1 -[dimethylaminoacetyl]-piperidine hydrochloride; 4-N-Hydroxy-carbamoyl]- 4

-[[

4 -methoxybenzene-sulfonyl(benzyl) amino]- I -[3-picolyl]-piperidine dihydrochloride; 4 -N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl) amino]- 1 -[carbomethoxymethyl]-piperidine hydrochloride; WO 00/04892 PCT/US99/13948 -71 4-N-Hydroxy-carbamoyl]-4-[[ 4 -methoxybenzene-sulfonyl(benzyl) amino]-1-piperidine trifluoroacetate; 4 -N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl) amino]- 1 -[t-butoxycarbonyl]-piperidine; 5 4-N-Hydroxycarbamoyl]-4-[[ 4 -methoxybenzene-sulfonyl(benzyl)-amino] 1-[methylsulfonyl]-piperidine; N-Hydroxycarbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino] 1-[4-picoly]-piperidine hydrochloride; N-Hydroxycarbamoyl]-4-[[ 4 -methoxybenzene-sulfonyl(benzyl)amino] 10 1-[morpholinocarbonyl]-piperidine hydrochloride; and N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl (benzyl)amino]-2-[2-(4 morpholino)ethyl]acetamide. The following compounds are prepared similarly to Example 7: N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl](isobutyl)-amino-2-(2-(4 15 morpholino)ethyl]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl]( 2 -picoly)-amino-2-(2-(4 morpholino)ethyl]acetamide dihydro-chloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[2-(4 morpholino)ethyl]acetamide dihydrochloride; 20 N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl](2-methyl-thiazol 4 -ylmethyl)amino]-2-[2-(4-morpholino) ethyl]acetamide dihydrochloride; N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl]benzyl)amino]-2-[2-(4 thiomorpholino]ethyl]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4 25 methylthiazol-4-ylmethyl]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl(benzyl)amino]-2-[(6 chloropiperonyl]acetamide; N-Hydroxy-2-[[4-methoxybenzenesulfonyl(benzyl)amino]-2-[(1 pyrazolyl)methyl]acetamide; 30 N-Hydroxy-2-[[4-methoxybenzenesulfonyl(3-picolyl)amino]-2-[3 picolyllacetamide; N-Hydroxy-2-[[ 4 -methoxybenzenesulfonyl(benzyl)-amino]-2-[(1-methyl 4 -imidazolyl)methyl]acetamide hydrochloride; WO 00/04892 PCTIUS99/13948 -72 N-Hydroxy-2-[[4-methoxybenzenesulfonyl(isobutyl)amino]-2-[(1-methyl 4-imidazolyl)methyl]acetamide hydrochloride; N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[( 1 methyl-4-imidazolyl)methyl]acetamide hydrochloride; 5 N-Hydroxy-2-[[4-methoxybenzenesulfonyl(2-picolyl)amino]-2-[( 1 methyl-4-imidazolyl)methyl]-acetamide hydrochloride; and N-Hydroxy-2-[[4-methoxybenzenesulfonyl] (2-methylthiazol 4-ylmethyl)amino-2-[(1-methyl- 4 -imidazolyl)methyl]acetamide hydrochloride. Another group of small peptide matrix metalloproteinase inhibitors are 10 described in United States Patent Numbers 5,270,326, 5,530,161, 5,525,629, and 5,304,604 (incorporated herein by reference). The compounds are hydroxamic acids defined by the formula 0 0 O R 3

R

4 HONHCCH-CH-CN-CHCOX and N R5 I I I I H 0 RI R 2

R

3

R

4 A CONHOH R SOn where R I, R 2 , R 3 , and R 4 can be hydrogen or alkyl and X is OR 5 or 15 NHR 5 where R 5 includes hydrogen, alkyl and aryl, A includes alkyl, and n is 0 to 2. Typical compounds to be employed in the instant method include the following: N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-D-tryptophan methylamide; 20 N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-N-methyl-L tryptophan methylamide;

N-[

2 -Isobutyl-3-(N-hydroxycarbonylamido)-propanoyl]-L-3-(2 naphthyl)-alanine methylamide;

N-[

2 -Isobutyl- 3 -(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan 25 2-hydroxyethylamide; WO 00/04892 PCTIUS99/13948 -73 N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan amylamide; N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan piperidinamide; 5 N-[ 2 -Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl-L-tryptophan dodecylamide; N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L tryptophan(S)-methylbenzylamide; N-[L-2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L 10 tryptophan(6-phenylmethoxycarbonyl-amino-hexyl- 1)amide; 2S-Hydroxy-3R-[1 S-( 3 -methoxy-2,2-dimethyl-propylcarbamoyl) 2,2-dimethyl-propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[l S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] 6-(4-chloro)phenyl-hexanohydroxamic acid; 15 2S-Hydroxy-3R-[l S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] octanohydroxamic acid; 2S-Hydroxy-3R-[l S-(pyridin-2-ylmethylcarbamoyl)-2,2-dimethyl propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[IS-(pyridin-3-ylmethylcarbamoyl)-2,2-dimethyl 20 propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[ l S-(pyridin-4-ylmethylcarbamoyl)-2,2-dimethyl propylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] 4-methoxy-butanohydroxamic acid; 25 2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] 4-benzyloxy-butanohydroxamic acid; 2S-Hydroxy-3R-[ I S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] 4-benzylthio-butanohydroxamic acid; 2S-Hydroxy-3R-[1 S-(methylcarbamoyl)-2,2-dimethyl-buten 30 3-ylcarbamoyl]-5-methyl-hexanohydroxamic acid; 2S-Hydroxy-3R-[ l S-(tert-butylcarbamoyl)-2,2-dimethyl propylcarbamoyl]-5-methyl-hexanohydroxamic acid; WO 00/04892 PCT/US99/13948 -74 2S-Hydroxy-3R-[ 1 S-(N,N-dimethyl-carbamoyl)-2,2-dimethylb propylcarbamoyl]-5-methyl-hexanohydroxamnic acid; 2S-Hydroxy-3R-[ 1S-(3 -hydroxy-2,2-dimethyl-propylcarbamoyl) 2

,

2 -dimethyl-propylcarbanoyl]-5-methyl-hexanohydroxamic acid; 5 2S-J-ydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl] 6-phenyl-hexanohydroxamic acid; 2 S-Hydroxy-3R-[ I S-(methylcarbamoyl)-2,2-dimethyl-butylcarbamoyl]. 5-methyl-hexanohydroxamic acid; [4-(N-Hydroxyamnino)-2R-isobutylsuccin-yl] -L-phenylalanine-N 10 (2-hydroxyethyl)-amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl] -L-phenylalaninyl-proline;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]pL-phenylalanine-N (2-hydroxyethyl)-N-methylamide;

[

4 -(N-Hydroxyamino)-2R-isobutylsucciny]-L-phenylalaninylD-proinol; 15 [4-(N-Hydroxyamnino)-2R-isobutylsuccinyl] -L-phenylalaninyl-L-prolinol;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N(5-N. methyl-pentylcarboxamide)amide;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N (2-ethylthioethyl)amide; 20 [ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N (2-methoxyethyl)amide;

[

4 -(N-Hydroxyamnino)-2R-isobutylsuccinyl]-L-phenylaanineN(2-N acetylethyl)amide;

[

4 -(N-Hydroxyamino)-2R-isobutysucciny]-L-phenylalanine-N. 25 (3 -(2-pyrrolidone)propyl)amide;

[

4 -(N-Hydroxyamnino)-2R-isobutylsuccinyl]-L-phenylalanine-N (3 -(2-pyrrolidone)propyl)amnide sodium salt;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine.N (2-acetoxyethyl)amide; 30 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-L-phenylalanine N-(3-(2-pyrrolidone)propyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-L-phenylalanine N-methyl-N-(2-hydroxyethyl)amide; WO 00/04892 PCT/US99/13948 -75 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-L-phenylalanine N-(2-hydroxyethyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-L-phenylalaninyl D-prolinol; 5 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-L-phenylalanine N-(3-(2-pyrrolidone)propyl)amide sodium salt; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methylsuccinyl]-L-phenylalanine N-(3-(2-pyrrolidone)propyl)amide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine 10 N-(3-(2-pyrrolidone)propyl)amide or a salt thereof;

N

2 -[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R isobutylsuccinyl]-N 6 -tert-butyloxycarbonyl-L-lysine-N 1 -methylamide;

N

2 -[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R isobutylsuccinyl]-N 6 -tert-butyloxycarbonyl-N 6 -(4-hydroxyphenylthiomethyl)-L 15 lysine-NI -methylamide;

N

2 - [4-(N-Hydroxyamino)-3 S -( 2 -thienylthiomethyl)-2R-isobutylsuccinyl] N6-tert-butyloxycarbonyl-L-lysine-N I-methylamide;

N

2 -[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R isobutylsuccinyl]-O-tert-butyl-L-threonine-N I-methylamide; 20 N 2 -[4-(N-Hydroxyamino)-3 S-(4-hydroxyphenylthiomethyl)-2R isobutylsuccinyl]-L-glutamine-N 1,N 5 -dimethylamide;

N

2 -[4-(N-Hydroxyamino)-3 S-(4-hydroxyphenylsulphonylmethyl)-2R isobutylsuccinyl]-N 6 -acetyl-L-lysine-N I-methylamide; 3R-(3-Methoxycarbonyl- I S-methylcarbamoyl-propylcarbamoyl) 25 5-methyl-2S-2-propenyl-hexanohydroxamic acid; 3R-(1 S-Methylcarbamoyl-2-thien-2-yl-ethylcarbamoyl)-5-methyl-2S 2-propenyl-hexanohydroxamic acid; 3R-(3-Methyl-i S-methylcarbamoyl-butylcarbamoyl)-5-methyl-2S 2-propenyl-hexanohydroxamic acid; 30 2S-[1 S-Methylcarbamoyl-2-oxadiazol-5-yl-ethylcarbamoyl)-5-methyl-2S 2-propenyl-hexanohydroxamic acid; WO 00/04892 PCT/US99/13948 -76

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxylic acid)phenylalanine-N-methylamide;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-N methylamide)phenylalanine-N-methylamide; 5 [ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-beta alanine)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L

(

4 -oxymethylcarboxyglycine)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-N 10 benzylamide)phenylalanine-N-methylamide;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-cyano)phenylalanine-N methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-acetamido) phenylalanine-N-methylamide; 15 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L

(

4 -oxymethylcarboxamide)-henylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethylsuccinyl]-L

(

4 -N-acetylamino)-henylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethylsuccinyl]-L 20 ( 4 -N-methylsuccinylamide)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl) succinyl]-L-( 4 -N-(methylsuccinylamide)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4 aminophenylthiomethylsuccinyl]-L-(4-N-(4-(4-oxobutanoic acid) 25 aminophenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl) succinyl]-L-( 4 -N-methylsuccinylamido)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl) succinyl]-L-(4-N-(4-(4-oxobutanoic acid)aminophenylalanine-N-methylamide; 30 [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L

(

4 -oxymethylcarboxymethyl)phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L (4-N-(oxymethylcarboxylic acid)phenylalanine-N-methylamide; WO 00/04892 PCT[US99/13948 -77 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(2-thienylthiomethyl)-succinyl]-L 4-oxymethylcarboxyglycyl methyl ester)-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(2-thienylthiomethyl)-succinyl]-L 4-oxymethylcarboxyglycine)phenylalanine-N-methylamide; 5 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl-succinyl] -L 4-(oxymethylcarboxyglycyl methyl ester)-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl)-succinyl]-L 4 -(oxymethylcarboxyglycine)-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl] -L-4-oxymethylnitrile) 10 phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L3-I( 1 -(2 methyloxycarbonyl)-ethyl)-4-methoxyphenylalanine-Nmethylamide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl] -L-3 -(hydroxymethyl) 4-methoxyphenylalanine-N-methylamide; 15 [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-methyl 4-methoxyphenylalanine-N-methylamide; 2-[Benzyl-(octane- 1 -sulfonyl)-amino]-N-hydroxy-acetamide; N-Hydroxy-2-[(2-methoxy-benzyl)-(octane- I -sulfonyl)-amino] -acetamide; 2- [(2-Ethoxy-benzyl)-(octane- 1 -sulfonyl)-amino] -N-hydroxy-acetamide; 20 N-Hydroxy-2- [(naphthalen-2-yl-methyl)-(octane- 1 -sulfonyl)-amino] acetamide; 2- [4-Chloro-benzyl)-(octane- 1 -sulfonyl)-amino] -N-hydroxy-acetamide;

N

2 -[3 S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinylyL-leucine.

N

1 -methylamide; 25 N 2 -[3 S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl)] -5-methyl-L glutamic acid-N 1 I -methylamide;

N

2 -[3 S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl)]-L phenylalanine -N 1 I -methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(thienylthiomethyl)succinyl]

-L

30 phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-phenylthiomethyl)succinyl]-L phenylaianine-N-methylamide; WO 00/04892 PCTIUS99/13948 -78 2S-(4-Methoxyphenylsulfanylmethyl)-3R-(2-phenyl- I S-methylcarbamoyl ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(3-Chlorophenylsulfanylmethyl)-3R-(2-phenyl-I S-methylcarbamoyl ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 5 2S-(Phenylsulfanylmethyl)-3R-(2-phenyl- I S-(pyrid-3 ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(3-Methylphenylsulfanylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2 S-(Thien-2-ylsulfanylmethyl)-3R-(2-(4-carboxymethoxyphenyl)-1

IS

10 methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(Thien-2-ylsulfanylmethyl)-3R-(2-phenyl-1S-(pyrid-3 ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(2-phenyl-1 S-(pyrid-3 ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 15 2S-(Thien-2-ylsulfanylmethyl)-3R-(2-naph-2-yl-1 S-methylcarbamoyl ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2

S-(

4 -Hydroxyphenylsulfanylmethyl)-3R-(2R-hydroxy- 1S methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(5-acetamido-I

S

20 methylcarbamoyl-pentylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(3-[1,1 dimethylethoxycarbonyl]-1 S-methylcarbamoyl-propylcarbamoyl)-5-methyl hexanohydroxamic acid; 2S-(Thien-2-ylsulfonylmethyl)-3R-(2-phenyl-I S-methylcarbamoyl 25 ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 3S-(2-[4-Acetamido-phenyl]-l S-methylcarbamoyl-ethylcarbamoyl) 5-methyl-hexanohydroxamic acid; 2S-(4-Phthalimido-butyl)-3R-(3-methyl-iS ethoxycarbonylmethylcarbamoyl-butylcarbamoyl)-5-methyl-hexanohydroxamic 30 acid; 3R-(2-[4-Methoxy-phenyl]-l S-methylcarbamoyl-ethylcarbamoyl) 2S,5-dimethyl-hexanohydroxamic acid; WO 00/04892 PCT/US99/13948 -79 3R-(2-Phenyl- 1 S-[2-oxo-pyrolid- 1 -yl]-propylcarbamoyl-ethylcarbam-oyl) 5-methyl-hexanohydroxamic acid; 3R-(2-[4-Methoxy-phenyl]- 1 S-methylcarbamoyl-ethylcarbamoyl) 5-methyl-hexanohydroxamic acid; 5 3R-(2-Phenyl- I S- [pyrid-3-ylmethylcarbamoyl] -ethylcarbamoyl)-5-methyl hexanohydroxamic acid; 3R-(2,2-Dimethyl- 1 S-methylcarbamoyl-propylcarbamoyl)-5methyl hexanohydroxamic acid; Isobutylmalonoyl-L-alanine-furfurylamide hydroxamate; 10 2-Isobutyl-3 -carbonyl-3 '-( 4 -acetylaniline)propionic acid; N-Benzyloxycarbonyl-a-phosphonoglycyliLalanine furfurylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(phenylthiomethyl)succinyl]

-L

phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(4-methoxyphenylthiomethyl) 15 succinyl]-L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(4-hydroxyphenylthiomethyl) succinyl] -L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(2,4-dimethylphenylthiomethyl) succinyl]-L-phenylalanine-N-methylamide; 20 [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(3-bromophenylthiomethyl) succinyl] -L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(3 -chiorophenyithiomethyl) succinyl]-L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(3 -methylphenylthiomethyl) 25 succinyl] -L-phenylalanine-N-methylamide; [4-(N-Hydroxyamino)-2R-isobutyl-3 S-(4-(N-acetyl)-amino phenylthiomethyl)succinyl] -L-phenylalanine-N-methylamide; r4-?N-Hydroxyamino)-2R-isobutyl-3 S-phenylsulphinylmethylsuccinyl]-L phenylalanine-N-methylamide; 30 3 R-(3 -Methoxycarbonyl- 1 S-methylcarbamoy1-propylcarbamoy1> 5-methyl-2S-phenylsulfanylmethyl- hexanohydroxamic acid; 3R-(3-Methoxycarbonyl- I S-methylcarbamoyl-propylcarbamoyl)> 5 -methyl- 2 S-(thien-2-ylsulfanylmethyl)-hexanohydroxamic acid; WO 00/04892 PCT/US99/13948 -80 2S-(4-Methoxy-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-

IS

methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2

S-(

4 -Amino-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-

IS

methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 5 2S-(Ethylsulfanylmethyl)-3R-(3-methoxycarbonyl- 1 S-methylcarbamoyl propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2 S-(Acetylsulfanylmethyl)-3R-(3-methoxycarbonyl- S-methylcarbamoyl propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(Benzylsulfanylmethyl)-3R-(3-methoxycarbonyl-IS-methylcarbamoyl 10 propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2 S-(tert-Butylsulfanylmethyl)-3R-(3-methoxycarbonyl-iS methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-Thiomethyl-3R-(3-methoxycarbonyl-I S-methylcarbamoyl propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 15 2

S-(

4 -Hydroxy-phenylsulfanylmethyl)-3R-(2-tert-butoxycarbonyl-

IS

methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxy-phenylsulphinylmethyl)-3R-(3-methoxycarbonyl-1S methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid; 2S-(4-Hydroxy-phenylsulphonylmethyl)-3R-(3-methoxycarbonyl- I S 20 methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[1-(2 aminoethyl)-pyrrolidine]amide;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[1-(3 aminopropyl)-2(RS)-methylpiperidine]amide; 25 [ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[2-(2 aminoethyl)- 1 -methylpyrrole] amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3 aminomethylpyridine)amide;

[

4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N 30 (2-aminomethylpyridine)amide; [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N (4-aminomethylpyridine)amide; WO 00/04892 PCTIUS99/13948 -81 [4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N (1 -(3-aminopropyl)-imidazole)amide;

[

4 -(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N (2-aminomethylbenzimdazole)amide; 5 [4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine N-[4-(2-aminoethyl)-morpholino]amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N [4-(2-aminoethyl)-morpholine]amide;

[

4 -(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenylalanine-N 10 [2-(2-aminoethyl)-pyridine]amide;

[

4 -(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenylalanine-N

[

4 -(2-aminopropyl)-morpholine]amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N (3-aminomethylpyridine)amide hydrochloride; and 15 [ 4 -(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N

[

4 -(2-aminoethyl)-morpholine]amide hydrochloride. In a preferred embodiment, tricyclic butyric acid derivatives which are inhibitors of matrix metalloprotienases are employed in the instant invention. A preferred group of tricyclic butyric acid derivatives are defined by the formula: W Z R W Y Z 2 20 R o X wherein one of R I or R2 s -C-CH-(CH)a-C-R5 | 1 25 R Ra wherein X is 0,

N-OR

6 wherein R 6 is hydrogen, -(CH2)n-aryl wherein n is zero or an integer of 1 to 5, alkyl, or 30 -(CH2)n-cycloalkyl wherein n is as defined above, or WO 00/04892 PCT/US99/13948 -82

N-N-R

6 wherein R 6 and R 6 a are each the same or different and R6a each is as defined above for R 6 ; 5 R and Ra are each the same or different and each is hydrogen, -(CH2)n-aryl wherein n is as defined above, -(CH2)n-heteroaryl wherein n is as defined above, -(CH2)p-R7-(CH 2 )q-aryl wherein R 7 is 0 or S and p or q is each zero or an integer of I to 5 and the sum of p + q equals an integer of 5, 10 -(CH2)p-R 7 -(CH2)q-heteroaryl wherein p, q, and R 7 are as defined above, alkyl, -(CH2)n-cycloalkyl wherein n is as defined above, or -(CH2)r-NH2 wherein r is an integer of I to 9; a is zero or an integer of I to 3; 15 R 5 is OH,

OR

6 wherein R 6 is as defined above,

NR

6 wherein R 6 and R 6 a are each R6a 20 the same or different and are as defined above for R 6 , or

NH-OR

6 wherein R 6 is as defined above;

R

3 and R 4 are each the same or different and each is hydrogen, alkyl,

NO

2 , 25 halogen,

OR

6 wherein R 6 is as defined above, CN, C0 2

R

6 wherein R 6 is as defined above, S0 3

R

6 wherein R 6 is as defined above, 30 CHO, WO 00/04892 PCT/US99/13948 -83 0 II -C-R wherein R is as defined above, 0 5 ||

-C-N-R

6 wherein R 6 and R 6 a are each the same or 11 R6a different and are as defined above for R 6 , or 10 -(CH2)n-N-R 6 wherein R 6 and R 6 a are each the same or R6a different and are as defined above for R 6 ; W, W I, Z, and ZI are each the same or different and each is CR 3 wherein R 3 is as 15 defined above, or N providing only one of W or WI is N and/or only one of Z or ZI is N; and Y is -N- wherein R is as defined above, 20 R -0-, -S-(O)m- wherein m is zero or an integer of I or 2, -CH2-, -C-, 25 0 -C- wherein R 6 is as defined above,

N-OR

6 30 -CH- wherein R 6 is as defined above,

OR

6 WO 00/04892 PCT/US99/13948 -84 -C- wherein R 6 and R 6 a are the same or different and are as defined

N-N-R

6 5 R6a above for R 6 , -C-N- wherein R 6 is as defined above, || 1 O R 6 10 -N-C- wherein R 6 is as defined above, il 1

R

6 0 -C-0-, 11 15 0 -O-C-, -CH2-0-, 20 -O-CH2-, -CH2-S(O)m- wherein m is as defined above, -S(O)m-CH2- wherein m is as defined above,

-CH

2 -N- wherein R 6 is as defined above, 25 R6

-N-CH

2 - wherein R 6 is as defined above, R6 -CH=N-, or 30 -N=CH-; with the proviso that when X is 0, and R 5 is not NH-OR 6 , at least one of R or Ra is not hydrogen; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Typical compounds from this class include: 35 4 -Dibenzofuran-2-yl-4-hydroxyimino-butyric acid; WO 00/04892 PCT/US99/13948 -85 2

-(

2 -Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-4-methyl-pentanoic acid; 2

-(

2 -Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-phenyl-pentanoic acid; 4 -Dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid; 5-(4-Chloro-phenyl)-2-(2-dibenzofuran-2-yl-2-hydroxyimino-ethyl) 5 pentanoic acid; 2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-fluoro-phenyl) pentanoic acid; 2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-methoxy-phenyl) pentanoic acid; 10 2

-(

2 -Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-p-tolyl-pentanoic acid; 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-methyl-hexanoic acid; 3 -(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-phenyl-hexanoic acid; 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-phenyl-pentanoic acid; 6-(4-Chloro-phenyl)-3-(dibenzofuran-2-yl-hydroxyimino-methyl) 15 hexanoic acid; 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-fluoro-phenyl) hexanoic acid; 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-methoxyphenyl) hexanoic acid; and 20 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-p-tolyl-hexanoic acid; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Tricyclic butyric acids having an a-amino substituent are defined by the formula: W ZNR 4

R

5 R C- CH 2

CHCOR

3 W Y 25 R2 wherein: /R7 X is 0, NOR 9 , S, OH, SH, or -N-N \R7a WO 00/04892 PCT/US99/13948 -86

R

7 and R7a independently are hydrogen, Cl-C 2 0 alkyl or substituted CI-C 2 0 alkyl, (CH2) 0

-

6 -aryl, 5 (CH2)0-6-heteroaryl, or (CH2)0-6-cycloalkyl;

R

1 and R2 independently are hydrogen,

CI-C

2 0 alkyl or substituted CI-C 2 0 alkyl, 10 halo,

NO

2 , CN, CHO,

COR

6 , 15

COOR

6 , S0 3

R

6 ,

OR

6 ,

CONR

4

R

5 , (CH2)0- 6 -aryl, 20 (CH2)0- 6 -heteroaryl, or (CH2)0-6-cycloalkyl;

R

6 is hydrogen, C I-C 2 0 alkyl or substituted C 1

-C

2 0 alkyl; aryl is phenyl or substituted phenyl; 25 R 3 is hydroxy, 0-CI -C 2 0 alkyl or substituted O-Cl -C 2 0 alkyl, 0-(CH2) 1

-

3 aryl, or

NHOR

6 ;

R

4 and R 5 independently are hydrogen, WO 00/04892 PCT/US99/13948 -87

C

1

-C

2 0 alkyl or substituted C 1

-C

2 0 alkyl, (CH2)0-6-aryl, (CH2)0-6-heteroaryl; or one of R4 and R 5 is hydrogen and the other is:

COR

8 , 5

CSR

8 ,

CONR

8

R

9 ,

CSNR

8

R

9 ,

COOR

8 ,

COSR

8 , 10

COCHR

8 ,

NR

1

R

2

CON-CONR

8

R

9 , 15

CON-COOR

8 ,

CON-COSR

8 , or 20 R1

CON-SO

2

NR

8

R

9 ; 25

CON-SO

3

R

8 ; Y is -N-, 30 RI -0-, -S(O)0, 1 or 2, -CH2-, WO 00/04892 PCT/US99/13948 -88 -C-, || 0 -C-, 5 ||

NOR

8 -CH-, 11 OR8 10 -C-, || N-N-R8R 9 -C-N-, II | 15 O R 8 -N-C-, I ||

R

8 0 -C-0, 20 || 0 -CH2-0-, -O-CH2-,

-CH

2

S(O)

0 , 1 or 2, 25

-S(O)

0 , 1 or 2-CH2-, -CH2-N-,

R

8 -N-CH2-, 30

R

8 -CH=N, or -N=CH-; R8 and R 9 independently are 35 hydrogen, C -C 2 0 alkyl or substituted C -C 2 0 alkyl, WO 00/04892 PCTIUS99/13948 -89 (CH2)0-6-aryl, (CH2)0-6-heteroaryl, or (CH2)0-6-cycloalkyl; W, W I, Z, and ZI independently are CR 1 or N; 5 and the pharmaceutically acceptable salts, isomers, stereoisomers, and solvates thereof. Specific examples of compounds to be employed in the present method include: (S)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric 10 acid; (R)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid;

(S)-

2 -Amino-4-dibenzofuran-2-yl-4-oxo-butyric acid;

(S)-

2 -Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric; 15 (S)-4-Dibenzofuran-2-yl-2-[3-( 2

,

6 -diisopropyl-phenyl)-ureido]-4-oxo butyric acid;

(S)-

2 -Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid;

(S)-

4 -Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid;

(S)-

4 -Dibenzofuran- 2 -yl-4-oxo-2-(3-phenyl-propionylamino)-butyric acid; 20 (S)- 4 -Dibenzofuran- 2 -yl-4-oxo-2-(7-phenyl-heptanoylamino)-butyric acid; (S)-2-[(Biphenyl-4-carbonyl)-amino]- 4 -dibenzofuran-2-yl-4-oxo-butyric acid;

(S)-

4 -Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid;

(S)-

4 -Dibenzofuran-2-yl-4-oxo-2-(dodecanoyl-amino)-butyric acid; 25 (S)- 4 -Dibenzofuran- 2 -yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid; (R)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid;

(S)-

2 -Amino-4-dibenzofuran-2-yl-4-oxo-butyric acid; 30 (S)- 2 -Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid; (S)-4-Dibenzofuran-2-yl-2-[3-( 2

,

6 -diisopropyl-phenyl)-ureido]-4-oxo butyric acid; WO 00/04892 PCT/US99/13948 -90

(S)-

2 -Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid;

(S)-

4 -Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid; (S)-4-Dibenzofuran-2-yl-4-oxo-2-(3-phenyl-propionylamino)-butyric acid; (S)-4-Dibenzofuran-2-yl-4-oxo-2-(7-phenyl-heptanoylamino)-butyric acid; 5 (S)-2-[(Biphenyl- 4 -carbonyl)-amino]-4-dibenzofuran-2-yl-4-oxo-butyric acid;

(S)-

4 -Dibenzofuran-2-yl-4-oxo-2-(octanoylamino)-butyric acid; and

(S)-

4 -Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid. Tricyclic sulfonamide matrix metalloproteinase inhibitors include 10 compounds of the formula 0 R21 R S=R X R4 M wherein M is a natural (L) alpha amino acid derivative having the structure CORI -N H H R X is 0, S, S(O)n, CH 2 , CO, or NH; 15 R is a side chain of a natural alpha amino acid; R I is CI-C 5 alkoxy, hydroxy, or -NHOR 5 ;

R

2 and R 4 are independently hydrogen, -CI-C 5 alkyl, -NO 2 , halogen, -OR 5 , -CN, -C0 2

R

5 , -S0 3

R

5 ,-CHO, -COR 5 , -CONR 5

R

6 , -(CH2)nNR 5

R

6 , -CF 3 , or

-NHCOR

5 ; 20 each R 5 and R 6 are independently hydrogen or CI-C 5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, ester, amides, and prodrugs thereof. Specific compounds from this class to be employed include:

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid; 25 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid; WO 00/04892 PCT/US99/13948 -91 (L)-2-(Dibenzofuran-2-sulfonylamino)-propionic acid; (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid; (Dibenzofuran-2-sulfonylamino)-acetic acid; (L)-2-(Dibenzofuran-2-sulfonylamino)-succinic acid; 5 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid; (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxyamide;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid; 10 (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-propionic acid;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid; (Dibenzofuran-2-sulfonylamino)-acetic acid; 15 (L)- 2 -(Dibenzofuran-2-sulfonylamino)-succinic acid; (L)-2-(Dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;

(L)-

2 -(Dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid; and (L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid hydroxyamide. 20 Additional tricyclic sulfonamides are defined by the formula: O 0 R X wherein Q is an un-natural amino acid; X is 0, S, S(O)n, CH 2 , CO, or NH;

R

2 and R 4 are independently hydrogen, CI-C 5 alkyl, -NO 2 , halogen, -OR 5 , -CN, 25 -C0 2

R

5 , -S0 3

R

5 , -CHO, -COR 5 , -CONR 5

R

6 , -(CH2)nNR 5

R

6 , -CF 3 , or

-NHCOR

5 ; each R 5 and R 6 are independently hydrogen or C 1

-C

5 alkyl; and WO 00/04892 PCT/US99/13948 -92 n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. Specific examples of such compounds include:

(S)-

2 -(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid; 5 2 (S)- 3 -[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid;

(S)-

2 -(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid; and 2 (S)- 3 -[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid. Another general class of matrix metalloproteinase inhibitors, which are useful to treat and prevent heart failure and ventricular dilatation, are biphenyl 10 butyric acid derivatives, including compounds of the formula: R23 4

/R

3

R

4 0 N I I II R\ -- C-C---C--C-R 5 R I ~ 3a R 4 a wherein R and R I are the same or different and are hydrogen, alkyl, 15 halogen, nitro, cyano, trifluoromethyl,

-OR

6 wherein R 6 is hydrogen, 20 alkyl, aryl, arylalkyl, heteroaryl, or cycloalkyl, 25 -N-R 6 wherein R 6 and R 6 a are the same or different and are as

R

6 a defined above for R 6

,

WO 00/04892 PCT/US99/13948 -93 0 1| -0-C-R 6 wherein R 6 is as defined above, 0 5 ||

-NH-C-R

6 wherein R 6 is as defined above, 0 -i

-S-C-R

6 wherein R 6 is as defined above, 10 -SR 6 wherein R 6 is as defined above, 0 -s

-C-R

6 wherein R 6 is as defined above,

-CH

2 -0R 6 wherein R 6 is as defined above, 15 -CH 2

-N-R

6 wherein R 6 and R 6 a are the same or different and are as R6a defined above for R 6 , 0 20 ||

-C-N-R

6 wherein R 6 and R 6 a are the same or different and are as R6a defined above for R 6 , 25 0 II

-S-R

6 wherein R 6 is as defined above, 11 30 cycloalkyl, or heteroaryl, with the proviso that R and R I are not both hydrogen;

R

2 is -OR 6 wherein R 6 is as defined above, or

-N-R

6 wherein R 6 and R 6 a are the same or different and are as 35 R6a defined above for R 6

;

WO 00/04892 PCT/US99/13948 -94

R

3 , R 3 a, R 4 , and R 4 a are the same or different and are hydrogen, fluorine, alkyl, 5 -(CH2)n-aryl wherein n is an integer from I to 6, (CH2)n-heteroaryl wherein n is as defined above, -(CH2)n-cycloalkyl wherein n is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is 0, S, SO, SO 2 , or NH, and p and q are each zero or an integer of I to 6, and the sum of p + q is not 10 greater than six, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, or -(CH2)n-R 7 wherein R 7 is N-phthalimido, 15 N-2,3-naphthyimido,

-OR

6 wherein R 6 is as defined above,

-N-R

6 wherein R 6 and R 6 a are the same or different and are as R6a 20 defined above for R 6 ,

-SR

6 where R 6 is as defined above, 0

-S-R

6 wherein R 6 is as defined above, 25 0

-S-R

6 wherein R 6 is as defined above, 11 30 0

-O-C-R

6 wherein R 6 is as defined above, WO 00/04892 PCT/US99/13948 -95 0

-N-C-R

6 wherein R 6 and R 6 a are the same or different and are as 5 R6a defined above for R 6 , 0

-S-C-R

6 wherein R 6 is as defined above, 10 0 II

-C-R

6 wherein R 6 is as defined above, 0 15

-C-OR

6 wherein R 6 is as defined above, or 0

-C-N-R

6 wherein R 6 and R 6 a are the same or different and are as 20 R6a defined above for R 6 , and n is as defined above;

R

5 is OH or SH; with the proviso that R 3 , R 3 a, R 4 , and R 4 a are hydrogen or at least one of R 3 , R 3 a, R 4 , or R 4 a is fluorine; and corresponding isomers 25 thereof; or a pharmaceutically acceptable salt thereof. Typical compounds from this class that are routinely utilized to treat atherosclerosis include: 4

-(

4 '-Chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4

-(

4 '-Bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 30 4

-(

4 '-Chloro-biphenyl-4-yl)-4-(dimethylhydrazono)-butyric acid; 4

-(

4 '-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;

(±)-

4

-(

4 '-Chloro-biphenyl-4-yl)-4-hydroxy-butyric acid; 4

-(

4 '-Bromo-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;

(±)-

4

-(

4 '-Chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid; 35 4

-(

2

',

4 '-Dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; WO 00/04892 PCT/US99/13948 -96 4

-(

2

',

4 1 -Difluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;

(±)-

4 -(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino2fluoro-2(3 phenylpropyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2..fluoro-2(2 5 phenylethyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino2fluoro-2(3 phthalimidopropyl)-butyric acid;

(±)-

4 -(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro.2 (phenylthiomethyl)-butyric acid; 10 4

-(

4 1 -Chloro- 2 '-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4 -Hydroxyimino-4-(4-'-trifluoromethy1.biphenylp4.yl>butyric acid; 4

-(

4 '-Chloro-biphenyl-4-yl)-4-methoxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-(1,3 -dioxo- 1,3 -dihydro isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid; 15 (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2( 1 H-indol 3 -yl)methyl-butyric acid;

(±)-

4

-(

4 '-Chloro-biphenyl-4-yl)-4-hydroxyimino2fluoro-2-methyl butyric acid;

(±)-

2

-[

2

-(

4 '-Chloro-bipheny1-4-y1)-2-hydroxyiminoethyl]y2-fluoro 20 6-phenyl-hexanoic acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-.[2-( 1,3-dioxo- 1,3 -dihydro benzo [F] isoindol- 2 -yl)-ethyl]-4-hydroxyimino-butyric acid;

(±)-

2

-[

2

-(

41 -Chloro-bipheny1-4-y1)-2-hydroxyiminoethy11..6-(1,3 -dioxo 1 ,3-dihydro-isoindol-2-yl)-2-fluoro-hexanoic acid; 25 (±)- 4

-(

4 '-Chloro-bipheny-4-y1)-4-hydroxyimino-2fluoro-2.[2{Phenyl1 ethylcarbamoyl)-ethyl] -butyric acid; 4-(4'-Chloro-biphenyl-4-yl)-3 ,3 -difluoro-4-hydroxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-3 ,3 -dimethyl-2-fluoro-4-hydroxyimino. butyric acid; 30 (±)- 4

-(

4 '-Chloro-bipheny1-4-yl)-2,2dimethy3fluoro-4-hydroxyimino butyric acid; WO 00/04892 PCT/US99/13948 -97 4

-(

4 '-Chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; and 4-(4'-Chloro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric acid. 5 A compound selected from the group consisting of: 4

-(

4 '-Chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4 -(4'-Bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4

-(

4 '-Chloro-biphenyl-4-yl)-4-(dimethylhydrazono)-butyric acid; 4

-(

4 '-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 10 (±)- 4

-(

4 '-Chloro-biphenyl-4-yl)-4-hydroxy-butyric acid; 4

-(

4 '-Bromo-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;

(±)-

4

-(

4 '-Chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid; 4

-(

2 ',4'-Dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4

-(

2

',

4 '-Difluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 15 (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3 phenylpropyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(2 phenylethyl)-butyric acid;

(±)-

4 -(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3 20 phthalimidopropyl)-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2 (phenylthiomethyl)-butyric acid; 4

-(

4 '-Chloro- 2 '-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4 -Hydroxyimino-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid; 25 4

-(

4 '-Chloro-biphenyl-4-yl)-4-methoxyimino-butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-(1,3-dioxo-1,3-dihydro isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid;

(±)-

4 -(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(I H-indol 3-yl)methyl-butyric acid; 30 (±)- 4

-(

4 '-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-methyl butyric acid; WO 00/04892 PCT/US99/13948 -98 (±)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-2-fluoro 6-phenyl-hexanoic acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-(1,3-dioxo- 1,3-dihydro benzo[F]isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid; 5 (±)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-(1,3-dioxo 1,3-dihydro-isoindol-2-yl)-2-fluoro-hexanoic acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-[2-(phenyl ethylcarbamoyl)-ethyl]-butyric acid; 4-(4'-Chloro-biphenyl-4-yl)-3, 3 -difluoro-4-hydroxyimino-butyric acid; 10 (±)-4-(4'-Chloro-biphenyl-4-yl)-3,3-dimethyl-2-fluoro-4-hydroxyimino butyric acid; (±)-4-(4'-Chloro-biphenyl-4-yl)-2,2-dimethyl-3-fluoro-4-hydroxyimino butyric acid; 4

-(

4 '-Chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; 15 and 4-(4'-Chloro-biphenyl-4-yl)-2,2,3, 3 -tetrafluoro-4-hydroxyimino-butyric acid. Biphenyl sulfonamides are also particularly good in the present method. Such compounds include those of the formula: 0 --- C-COR 3 20 R 2 wherein: RI is CI-C 6 alkyl, halo, nitro, NR 4

R

5 , cyano, OR 4 , and COOR 4 ;

R

2 is CI-C 6 alkyl, optionally substituted by phenyl, substituted phenyl, NR 4

R

5 , NH 25

OR

6 , carboxy, carboxamido,

H

2 N-C-NH-, thio, methylthio, indole, imidazole, phthalimido, phenyl, and substituted phenyl;

R

3 is OH, OCI-C 6 alkyl, or NHOH;

R

4 is hydrogen, CI-C 6 alkyl, or CI-C 6 alkanoyl; WO 00/04892 PCT/US99/13948 -99

R

5 is hydrogen or CI-C 6 alkyl; and

R

6 is hydrogen, CI-C 6 alkyl, CI-C 6 alkanoyl, phenyl, or substituted phenyl. Specific compounds which can be employed include a compound of the above formula wherein R I is at the 4' position. 5 Another class of matrix metalloproteinase inhibitors useful in the present method are the heterocyclic substituted phenyl butyric acid derivatives, for example those defined by the formula: 0 Ar-Y N Z (W)n R4 R R2 R3 Ar is selected from phenyl, 10 phenyl substituted with alkyl,

NO

2 , halogen,

OR

5 wherein R 5 is hydrogen or alkyl, 15 CN, C0 2

R

5 wherein R 5 is as defined above, S0 3

R

5 wherein R 5 is as defined above, CHO,

COR

5 wherein R 5 is as defined above, 20 CONHR 5 wherein R 5 is as defined above, or

NHCOR

5 wherein R 5 is as defined above, 2-naphthyl, or heteroaryl; RI is selected from hydrogen, 25 methyl, ethyl,

NO

2

,

WO 00/04892 PCTIUS99/13948 -100 halogen,

OR

5 wherein R 5 is as defined above, CN, C0 2

R

5 wherein R 5 is as defined above, 5 S0 3

R

5 wherein R 5 is as defined above, CHO, or

COR

5 wherein R 5 is as defined above;

R

2 and R 3 are the same or different and independently selected from hydrogen, alkyl, 10 -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is 0 or S and p and q is each zero or an integer of I to 5, and the sum of p + q is not 15 greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above,

-(CH

2 )tNR 6

R

6 a, wherein t is zero or an integer of from I to 9 and

R

6 and R 6 a are each the same or different and are as 20 defined above for R 5 , -(CH2)vSR 5 , wherein v and R 5 are as defined above, -(CH2)vCO 2

R

5 , wherein v and R 5 are as defined above, or

-(CH

2 )vCONR 6

R

6 a, wherein R 6 and R 6 a are the same or different 25 and are as defined above for R 5 and v is as defined above;

R

3 is additionally -(CH2)rR 7 wherein r is an integer from I to 5 and R 7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo benzo[f]isoindol-2-yl; Y is CH or N; WO 00/04892 PCT/US99/13948 -101 ~OH Z is C 110 ' R wherein R 10 is as defined above for R 2 and R 3 , and is independently the same or different from R 2 and R 3 provided that when 1OH Z is C R 1 0 I then R 4 must be OH, 5 C=O,

C=NOR

5 wherein R 5 is as defined above, or

C=N-NR

6

R

6 a wherein R 6 and R 6 a are the same or different and are as defined above for R 5 ; W is -CHR 5 wherein R 5 is as defined above; 10 n is zero or an integer of 1;

R

4 is OH,

NR

6

R

6 a wherein R 6 and R 6 a are the same or different and are as defined above for R 5 , when R 4 is NR 6

R

6 a then Z must be C=O or

NHOR

9 wherein R 9 is hydrogen, alkyl, or benzyl; 15 and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Especially preferred MMP inhibitors have the formula /--\ -0 Ar-Y N Z 1 (W)n 3R4 R R2 R Ar is selected from phenyl, phenyl substituted with 20 alkyl,

NO

2 , halogen,

OR

5 wherein R 5 is hydrogen or alkyl, CN, 25 C0 2

R

5 wherein R 5 is as defined above, WO 00/04892 PCT/US99/13948 -102 S0 3

R

5 wherein R 5 is as defined above, CHO,

COR

5 wherein R 5 is as defined above,

CONHR

5 wherein R 5 is as defined above, or 5

NHCOR

5 wherein R 5 is as defined above, 2-naphthyl, or heteroaryl; RI is selected from hydrogen, methyl, 10 ethyl,

NO

2 , halogen,

OR

5 wherein R 5 is as defined above, CN, 15 C0 2

R

5 wherein R 5 is as defined above, S0 3

R

5 wherein R 5 is as defined above, CHO, or

COR

5 wherein R 5 is as defined above;

R

2 and R 3 are the same or different and independently selected from hydrogen, 20 alkyl, -(CH2)v-aryl wherein v is an integer from I to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is 0 or S and p and q is 25 each zero or an integer of I to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, WO 00/04892 PCT/US99/13948 -103

-(CH

2 )tNR 6

R

6 a, wherein t is zero or an integer of from I to 9 and R 6 and R 6 a are each the same or different and are as defined above for R 5 , -(CH2)VSR 5 , wherein v and R 5 are as 5 defined above, -(CH2)vCO2R 5 , wherein v and R 5 are as defined above, or

-(CH

2 )vCONR 6

R

6 a, wherein R 6 and R 6 a are the same or different and are as defined above for R 5 and v is as defined above; 10 R 3 is additionally -(CH2)rR 7 wherein r is an integer from 1 to 5 and R 7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo benzo[flisoindol-2-yl; Y is CH or N; 7 OH Z is C 10' 15 wherein R 10 is as defined above for R 2 and R 3 , and is independently the same or different from R 2 and R 3 provided that when 1OH Z is C 10 ' then R 4 must be OH, C=O,

C=NOR

5 wherein R 5 is as defined above, or 20 C=N-NR 6

R

6 a wherein R 6 and R 6 a are the same or different and are as defined above for R 5 ; W is -CHR 5 wherein R 5 is as defined above; n is zero or an integer of 1;

R

4 is OH, 25 NR 6

R

6 a wherein R 6 and R 6 a are the same or different and are as defined above for R 5 , when R 4 is NR 6

R

6 a then Z must be C=O or

NHOR

9 wherein R 9 is hydrogen, alkyl, or benzyl; WO 00/04892 PCT/US99/13948 -104 and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. Preferred compounds to be employed include: 4 -Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid; 4 -Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt; 5 N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide; E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid; E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin- I -yl)-phenyl]-butyric acid; 4 -Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; 10 (±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid; 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid; 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt; N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin- I -yl)-phenyl]-butyramide; E/Z-4-Hydroxyimino-4- [4-(4-phenyl-piperidin- I -yl)-phenyl] -butyric acid; 15 E/Z- 4 -Benzyloxyimino-4-[4-(4-phenyl-piperidin- I -yl)-phenyl]-butyric acid; 4 -Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and (±)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid. A compound which is 4 -oxo- 4 -[4-(4-phenyl-piperidin-1 -yl)-phenyl] 20 butyric acid. Similar compounds which are sulfonamide derivatives have the formula: 0 0 04 Ar-(CH 2 )m-YYN / (CH)z-S-N-(W R Ra wherein: Ar is selected from phenyl; 25 phenyl substituted with alkyl, -NO- 2 , halogen, -OR 5 , -CN, -C0 2

R

5 , -S0 3

R

5 , -CHO, -COR 5 , -CONHR 5 , -NHR 5 , or -NHCOR 5 ; heteroaryl; or 2-naphthyl; WO 00/04892 PCT/US99/13948 -105 RI is hydrogen, methyl, -NO 2 , -Cl, -NH 2 , -NHCO 2

CH

3 , -OH, or -CO 2 H;

R

2 and R 3 are the same or different and are independently selected from hydrogen, alkyl, -(CH2)v-aryl, -(CH2)v-heteroaryl, -(CH2)v-cycloalkyl, -(CH2)p-X-(CH2)q-aryl, -(CH2)p-X-(CH2)q-heteroaryl,

-(CH

2 )tNR 6

R

6 a, 5 -(CH2)vR 7 , -(CH2)vCO2R 5 , -(CH 2 )vCONR 6

R

6 a, or -(CH2)vSR 5 ; m is zero or 1; Y is CH or N; provided that when m = 1, Y does not = N; z is zero or 1; W is -CHR 8 ; 10 n is zero or 1;

R

4 is -OH, -NR 6

R

6 a, or -NHOR 9 ;

R

5 is hydrogen or alkyl; v is Ito 5; X is 0 or S; 15 p and q are independently 1 to 5, provided that p + q is not greater than 5; t is 1 to 9;

R

6 and R 6 a are each the same or different and are hydrogen or alkyl;

R

7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3-dihydro-1,3-dioxo benzo[fJisoindol-2-yl; 20 R 8 is hydrogen or alkyl; and

R

9 is hydrogen, alkyl, or benzyl; or a pharmaceutically acceptable salt thereof. Specific sulfonamide derivatives to be employed in the present method include: 25 [4-(4-Phenyl-piperidin- I -yl)-benzenesulfonylamino] -acetic acid; N-Hydroxy-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] acetamide; 3-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid; WO 00/04892 PCTIUS99/13948 -106 (R)-4-Methyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] pentanoic acid; (S)-4-Methyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] pentanoic acid; 5 (S)-3-Phenyl-2-[4-(4-phenyl-piperidin- 1 -yl)-benzenesulfonylamino] propionic acid; (R)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] propionic acid; (S)-3-(1H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1 -yl) 10 benzenesulfonylamino]-propionic acid; (±)-5-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] pentanoic acid; [4-(4-Phenyl-piperazin-1-yl)-benzene-sulfonylamino]-acetic acid; { Isobutyl-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonyl]amino } -acetic 15 acid; (S)-4-Phenyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] butyric acid; (R)-2-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-3 tritylsulfanyl-propionic acid, sodium salt; 20 (R)-3-(1H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1 -yl) benzenesulfonylamino]-propionic acid, disodium salt, monohydrate; (S)-2-{ 4 -[-4-(4-Hydroxy-phenyl)-piperazin- 1-yl] benzenesulfonylamino}-3-phenyl-propionic acid;

(S)-

2 -{4-[-4-(4-Chloro-phenyl)-piperazin-1-yl] 25 benzenesulfonylamino}-3-phenyl-propionic acid, hydrochloride; (R)-3-Mercapto-2-[4-(4-phenyl-piperidin-1-yl) benzenesulfonylamino]-propionic acid, trifluoracetic acid salt; (S)-2-[4-(4-Benzyl-piperidin-1-yl)-benzenesulfonylamino]-3-phenyl propionic acid; 30 (S)-3-(4-Benzyloxy-phenyl)-2-[ 4 -(4-phenyl-piperidin-1-yl) benzenesulfonylamino]-propionic acid; WO 00/04892 PCTIUS99/13948 -107 (S)-3-(4-Hydroxy-phenyl)-2-[4-(4-phenyl-piperidin- -yl) benzenesulfonylamino]-propionic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperazin-1-yl)-benzenesulfonylamino] propionic acid; 5 (S)-2-{4-[-4-(3-Methoxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino} 3-phenyl-propionic acid; (S)-2-{4-[-4-(3-Hydroxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino} 3-phenyl-propionic acid hydrobromide; (S)-2-{ 4 -[-4-(4-Methoxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino} 10 3-phenyl-propionic acid; (R)-4-Methyl-2-[4-(4-phenyl-piperidin- 1 -yl)-benzenesulfonylamino] pentanoic acid; (S)-4-Methyl-2-[4-(4-phenyl-piperidin-I -yl)-benzenesulfonylamino] pentanoic acid; 15 (S)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] propionic acid; (R)-3-Phenyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] propionic acid; (S)-3-(1H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl) 20 benzenesulfonylamino]-propionic acid; [4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid; N-Hydroxy-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] acetamide; 3-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid; 25 (R)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] pentanoic acid; (S)-4-Methyl-2-[4-(4-phenyl-piperidin- 1 -yl)-benzenesulfonylamino] pentanoic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] 30 propionic acid; (R)-3 -Phenyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] propionic acid; WO 00/04892 PCTIUS99/13948 -108 (S)-3-(1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin- 1-yl) benzenesulfonylamino]-propionic acid; (±)-5-Phenyl-2-[4-(4-phenyl-piperidin- 1 -yl)-benzenesulfonylamino] pentanoic acid; 5 [4-(4-Phenyl-piperazin- I -yl)-benzene-sulfonylamino] -acetic acid; { Isobutyl- [4-(4-phenyl-piperidin- 1 -yl)-benzenesulfonyl]amino} -acetic acid; (S)-4-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] butyric acid; 10 (R)-2-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-3 tritylsulfanyl-propionic acid, sodium salt; (R)-3-(1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin- 1-yl) benzenesulfonylamino]-propionic acid, disodium salt, monohydrate; (S)-2-{ 4 -[-4-(4-Hydroxy-phenyl)-piperazin-1-yl] 15 benzenesulfonylamino}-3-phenyl-propionic acid; (S)-2-{4-[-4-(4-Chloro-phenyl)-piperazin-1-yl] benzenesulfonylamino}-3-phenyl-propionic acid, hydrochloride; (R)-3-Mercapto-2-[4-(4-phenyl-piperidin-1-yl) benzenesulfonylamino]-propionic acid, trifluoracetic acid salt; 20 (S)-2-[4-(4-Benzyl-piperidin- 1 -yl)-benzenesulfonylamino]-3-phenyl propionic acid; (S)-3-( 4 -Benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin- -yl) benzenesulfonylamino]-propionic acid; (S)-3-(4-Hydroxy-phenyl)-2-[ 4 -(4-phenyl-piperidin-1-yl) 25 benzenesulfonylamino]-propionic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperazin- I -yl)-benzenesulfonylamino] propionic acid; (S)-2-{4-[-4-(3-Methoxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino} 3-phenyl-propionic acid; 30 (S)-2-{ 4

-[-

4 -(3-Hydroxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino} 3-phenyl-propionic acid hydrobromide; WO 00/04892 PCT/US99/13948 -109 (S)-2-f{4-[-4-(4-Methoxy-phenyl)-piperazin- I-yl]-benzenesulfonylamino} 3-phenyl-propionic acid; (R)-4-Methyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] pentanoic acid; 5 (S)-4-Methyl-2-[4-(4-phenyl-piperidin- 1 -yl)-benzenesulfonylamino] pentanoic acid; (S)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino] propionic acid; (R)-3-Phenyl-2-[4-(4-phenyl-piperidin- I -yl)-benzenesulfonylamino] 10 propionic acid; and (S)-3-(1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin- 1-yl) benzenesulfonylamino]-propionic acid. Additional specific compounds which can be used include: 2 -(Dibenzofuran-2-sulfonylamino)-3-(4-fluoro-phenyl)-propionic acid; 15 2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid; 3-( 4 -tert-Butoxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic acid; (Dibenzofuran-2-sulfonylamino)-phenyl-acetic acid; 3-tert-Butoxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid; 20 2-(Dibenzofuran-2-sulfonylamino)-3-(1H-imidazol-4-yl)-propionic acid; 2-(Dibenzofuran-2-sulfonylamino)-3-hydroxy-propionic acid; 3 -Benzyloxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid; 6 -Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid; 25 5-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoic acid; (Dibenzofuran-2-sulfonylamino)-(4-methoxy-phenyl)-acetic acid; 3-Chloro-2-(dibenzofuran-2-sulfonylamino)-propionic acid; 3-( 4 -Benzyloxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic 30 acid; 2 -(Dibenzofuran- 2 -sulfonylamino)-5-p-tolyl-sulfanylamino-pentanoic acid; 2 -(Dibenzofuran-2-sulfonylamino)-4-mercapto-butyric acid; WO 00/04892 PCT/US99/13948 -110 3

-(

4 -Bromo-phenyl)-2-(dibenzofuran-2-sulfonyl-amino)-propionic acid; 2 -(Dibenzofuran-2-sulfonylamino)-butyric acid; 1-(Dibenzofiran-2-sulfonylamino)-cyclopropane-carboxylic acid; 3

-(

4 -Chloro-phenyl)-2-(dibenzofuran-2-sulfonyl-amino)-propionic acid; 5 2-(Dibenzofuran-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-fluoro benzenesulfonylamino)-hexanoic-acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(4-methoxy benzenesulfonylamino)-hexanoic acid; 10 6

-(

4 -Bromo-benzenesulfonylamino)-2-(4'-bromo-biphenyl-4 sulfonylamino)-hexanoic-acid; 6

-(

2 -Acetylamino-thiazole-5-sulfonylamino)-2-(4'-bromo-biphenyl 4-sulfonylamino)-hexanoic-acid; 6

-(

4 -Acetylamino-benzenesulfonylamino)-2-(4'-bromo-biphenyl 15 4-sulfonylamino)-hexanoic-acid; 6 -Benzenesulfonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino) hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(pentane-1 -sulfonylamino) hexanoic acid; 20 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-2-sulfonylamino) hexanoic-acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(naphthalene- 1 sulfonylamino)-hexanoic-acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenyl 25 ethenesulfonylamino)-hexanoic-acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-phenyl-acetylamino-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-chloro-phenoxy) acetylamino]-hexanoic acid; 30 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-chloro-phenoxy) 2 -methyl-propionylamino]-hexanoic acid; WO 00/04892 PCT/US99/13948 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6- [2-(pyridin-4-ylsulfanyl) acetylamino] -hexanoic acid; 2 -(4'-Bromo-biphenyl-4-sulfonyamino)-6[2(2,4dichorophenoxy) acetylamino]-hexanoic acid; 5 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-thiophe-2-yl acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(3 -phenyl-acryloylamino) hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(7-phenyl-heptanoylamino) 10 hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[1 2 -(2-trifluoromethyl-phenyl) acetylamino]-hexanoic acid; 2

-(

4 '-Bromo-biphenyI-4-sulfonylamino)-6-(2-phenoxy-butyrylamino) hexanoic acid; 15 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenyl-sulfanyl acetylamino)-hexanoic acid; 2

-(

41 -Bromo-bipheny1-4-sulfonylamino)-6-(2phenoxyacetylamino) hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6- [2-(3 ,4-dimethoxy-phenyl) 20 acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[ 2 -(4-tert-butyl-phenoxy) acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-& 13 -(3 ,4-dimethoxy phenyl)-propionylamino]-hexanoic acid; 25 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent- I -enyl acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-

[

2 -(4-methoxy-phenoxy) acetylamino]-hexanoic acid; 2

-(

4 1 -Bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen- I -yloxy) 30 acetylamino]-hexanoic acid; WO 00/04892 PCT/US99/13948 -112 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy) acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl phenoxy)-butyrylamino]-hexanoic acid; 5 2 -(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl) propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino) hexanoic acid; 6-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4 10 sulfonylamino)-hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino) hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tert-butyl-phenoxy) acetylamino]-hexanoic acid; 15 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl) propionylamino]-hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent- I -enyl acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy) 20 acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen- I -yloxy) acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy) acetylamino]-hexanoic acid; 25 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl phenoxy)-butyrylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl) propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino) 30 hexanoic acid; WO 00/04892 PCT/US99/13948 -113 6-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4 sulfonylamino)-hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino) hexanoic acid; 5 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-nitro-phenyl) butyrylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tert-butyl-phenoxy) acetylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl) 10 propionylamino]-hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent-1 -enyl acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy) acetylamino]-hexanoic acid; 15 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(4-phenyl-butyrylamino) hexanoic acid; 2 -(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl phenoxy)-butyrylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenyl) 20 propionylamino]-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl) propionylamino]-hexanoic acid; 2 -(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino) hexanoic acid; 25 6-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4 sulfonylamino)-hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2-naphthalen- -yl acetylamino)-hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenoxy) 30 propionylamino]-hexanoic acid; WO 00/04892 PCT/US99/13948 -114 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(6-phenyl-hexanoylamino) hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-thiophen-2-yl butyrylamino)-hexanoic acid; 5 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-(2,4,6-triisopropyl benzoylamino)-hexanoic acid; 2

-(

4 '-Bromo-biphenyl-4-sulfonylamino)-6-isobutoxycarbonylamino hexanoic acid; 2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(9H-fluoren-9 10 ylmethoxycarbonylamino)-hexanoic acid; 6-(Adamantan- I -yloxycarbonylamino)-2-(4'-bromo-biphenyl-4 sulfonylamino)-hexanoic acid; and 6 -Allyloxycarbonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino) hexanoic acid. 15 Numerous succinamide MMP inhibitors are known and can be utilized in the method of this invention. Typical succinamides include: 2S,NI -Dihydroxy-3R-isobutyl-N 4 -{ I S-[ 2 -(2-methoxy-ethoxymethoxy) ethylcarbamoyl]-2,2-dimethyl-propyl}-succinamide; 2S-Allyl-Ni-hydroxy-3R-isobutyl-N 4 -{ I S-[2-(2-methoxy 20 ethoxymethoxy)ethylcarbamoyl] -2-phenyl-ethyl } -succinamide; 2S-Allyl-N 1 -hydroxy-3R-isobutyl-N 4 -{ 1S-[2-(2-methoxy ethoxymethoxy)ethylcarbamoyl]-2,2-dimethyl-propy } -succinamide; 2S-Allyl-N 1 -hydroxy-3R-isobutyl-N 4 -(l S- { 2-[2-(2-methoxy-ethoxy) ethoxy]-ethylcarbamoyl]-2,2-dimethyl-propyl } -succinamide; 25 2S-Allyl-N 4 - { 1 S-[ 2

,

2 -di-(methoxymethyl)-propylcarbamoy } -2,2 dimethyl-propyl]-NI -hydroxy-3R-isobutyl-succinamide; 2S-Allyl-N 4 -f{ IS-[2,2-di-(methoxymethyl)-butylcarbamoyl]-2,2-dimethyl propyl } -NI -hydroxy-3R-isobutyl-succinamide;

N

4 -Hydroxy-2R-isobutyl-N I-{ I S-[2-(2-methoxy-ethoxy) 30 ethylcarbamoyl]-2,2-dimethyl-propyl } -3 S-(thiophen-2-yl-sulfanylmethyl) succinamide; WO 00/04892 PCT/US99/13948 -115

N

4 -Hydroxy-2R-isobutyl-N I -(I S-f 2

-[

2 -(2-methoxy-ethoxy)-ethoxy] ethylcarbamoyl }-2,2-dimethyl-propyl)-3 S-(thiophen-2-yl-sulfanylmethyl) succinamide; NI-f {S- [ 2

,

2 -Di-(methoxymethyl)-propylcarbamoyl] -2,2-dimethyl 5 propyl }-N 4 -hydroxy-3R-isobutyl-3 S-(thiophen-2-yl-sulfanylmethyl) succinamide;

N

4 -Hydroxy-2R-isobutyl-N - { IS- [2-(2-methoxy-ethoxy) ethylcarbamoyl]-2,2-dimethyl-propyl }-3 S-propyl-succinamide;

N

4 -( I S-Cyclobutylcarbamoyl-2,2-dimethyl-propyl)-2S,N I -dihydroxy-3R 10 isobutyl-succinamide;

N

4 -( I S-CyclopropylcarbamoyI-2,2-dimethy1-propyl>2S ,N I -dihydroxy 3 R-isobutyl-succinamide;

N

4 -( 1 S-Cyclopentylcarbamoyl-2,2-dimethyl-propyl).2S,N I dihydroxy 3 R-isobutyl-succinamide; 15 N 4 -( 1 S-Cyclohexylcarbamoyl-2,2-dimethyl-propyl)-2 S,N I -dihydroxy-3R isobutyl-succinamide;

N

4 -( 1 S-Cycloheptylcarbamoyl-2,2-dimethyl-propyl).2S,N I -dihydroxy 3R-isobutyl-succinamide;

N

4 -( 1 S-Cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)..2S,N 1.. 20 dihydroxy-3R-isobutyl-succinamide;

N

4 -( I S-Cyclopropylcarbamoy1-2,2-dimethyl-propy1-2S ,N I -dihydroxy 3 R-(3 -phenyl-propenyl)-succinamide;

N

4 -( I S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl).2SN I dihydroxy. 3 R-(3 -phenyl-propyl)-succinamide; 25 N 4 - [2,2-Dimethyl- 1 S-( 2 -phenyl-cyclopropylcarbamoyl)-propyl] -2S,N I dihydroxy-3R-isobutyl-succinamide; 2S-Allyl-N 4 -( 1 -cyclopropylcarbamoy1-2,2-dimethyl-propy1-NlI -hydroxy 3R-isobutyl-succinamide; 2S-Allyl-N 4 -( 1 S-cyclopropylcarbamoyl-2-mercapto2methyl-propyl)-N I 30 hydroxy-3R-isobutyl-succinamide; WO 00/04892 PCT/US99/13948 -116

N

4 -(I S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N 1 -hydroxy-3R isobutyl-2S-(thiophen-2-ylsulfanylmethyl)-succinamide;

N

4 -(1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N I-hydroxy-2S (4-hydroxy-phenylsulfanylmethyl)-3R-isobutyl-succinamide; and 5 N 4 -(1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S-(1,3-dioxo 1,3-dihydro-isoindol-2-ylmethyl)-N1 -hydroxy-3R-isobutyl-succinamide. Another especially preferred group of MMP inhibitors to be utilized in the method of this invention are the sulfonated amino acid derivatives described in WO 97/27174, incorporated herein by reference. Those compounds have the 10 general structure 11

R

1 5~~ RI- R13 SQgN COY R2 where R I I is substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaryl alkyl; 15 R 12 is hydrogen, or a group as defined for R 1 1;

R

13 is a single bond, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R

14 is a single bond, -(CH 2

)

1 or 2-, -CH=CH-, -C=C-, -CO-, -CONH-, -N=N-, NH, N-alkyl, -NHCONH-, -NHCO-, -0-, -S-, -SO 2 NH-, -SO 2 NH-N=CH-, 20 or tetrazoldiyl;

R

15 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocyclic group; and Y is NHOH or OH. Especially preferred compounds to be employed in the method of this 25 invention have the above formula wherein R 13 is phenylene or substituted phenylene. Typical of such compounds that can be employed have the formula WO 00/04892 PCT/US99/13948 -117 Rl N=N R1 N 0 2 N COOH R12 where R I I and R 12 are as defined above, and R 17 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Especially preferred are compounds of the formula 181 5

R

1 8

SO

2 NH COOH wherein R I and R 18 are as follows: RII iR 1 8 CH2 H CH2 \ 0CH2

CF

3

CH

2 N \/ CH2 WO 00/04892 PCT[US99/13948 RII R 1 8 HOOC-CH 2 \/ \/ H (CH 3

)

2 CH- H 3 C - / (CH 3

)

2 CH F 3 c \/CH 2 F-0 0 (CH 3

)

2 CH- \0/ 0\ H Cf LICH 2 _- HO-O (CH 3

)

2 CH Br / \ / O

CH

WO 00/04892 PCT/US99/13948 -119 R II R1I8 H I 'CH 2 N N

(CH

3 2 CH- Br S-N 0

(CH

3 2 CH- C EC

CH

2 ~ HS C~C

(CH

3

)

2 CH -N N The following patents and applications covering MMP inhibitors are incorporated herein by reference: United States 5,753,653; WO 96/16027; WO 97/20824; WO 98/50348; WO 98/43963; WO 9832748; WO 98/17643; and 5 EP 0780386. These include compounds such as shown below. 4-[ 2 -(2-Carboxymethyl-4-phenyl-butylamino)-3 cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-methyl butyrylamino]-benzoic acid methyl ester; WO 00/04892 PCT/US99/13948 -120 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl butyrylamino]-benzoic acid methyl ester; 4 -[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3 dimethyl-butyrylamino]-benzoic acid methyl ester; 5 4-[2-(2-Carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl butyrylamino]-benzoic acid methyl ester; 4-[ 2 -(2-Hydroxaminocarbonylmethyl-5-methyl-valerylamino)-3,3 dimethyl-butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-2 10 cyclohexylpropionylamino]benzoic acid methyl ester; 4-[ 2

-(

2 -Carboxymethyl-4-methyl-valerylamino)-4-methyl-valerylamino] benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-phenyl-valerylamino)-3,3-dimethyl butyrylamino]-benzoic acid methyl ester; 15 4-[ 2 -(2-Carboxymethyl-4-methyl-pentanoylamino)-3-(1H-indol-3-yl) propionylamino-benzoic acid methyl ester; 5-Methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca 12(19),13,15,17-tetraen- I 0-ylcarbamoyl)-hexanoic acid; 4-[ 2

-(

2 -Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3-methyl 20 butyrylamino]-benzoic acid methyl ester; 4-[ 2

-(

2 -Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-2 cyclohexylpropionylamino]-benzoic acid methyl ester benzoic acid methyl ester; 4-[ 2

-(

2 -Hydroxaminocarbonylmethyl-4-methyl-valerylamino)-4-methyl valerylamino]-benzoic acid methyl ester; 25 4-[ 2 -(2-Hydroxaminocarbonylmethyl-4-phenyl-butylamino)-3 cyclohexylpropionylamino]benzoic acid methyl ester; 4-[ 2 -(2-Methoxyaminocarbonylmethyl-4-phenyl-butylamino)-3 cyclohexylpropionylamino]benzoic acid methyl ester; 4

-[

2

-(

2 -Hydroxaminocarbonylmethyl-5-phenyl-valerylamino)-3,3 30 dimethyl-butyrylamino]-benzoic acid methyl ester; 5-Methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0 13,18]nonadeca 12(19),13,15,17-tetraen- I 0-ylcarbamoyl)- I -hexylhydroxamic acid; WO 00/04892 PCT/US99/13948 -121 4-[ 2

-(

2 -Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)-3-(1

H

indol-3-yl)-propionylamino]-benzoic acid methyl ester; 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl-1-phenylcarbamoyl propylcarbamoyl]-5-methyl-hexanoic acid; 5 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl-1 -phenylcarbamoyl propylcarbamoyl]-5-methyl-hexanoic acid N-hydroxyamide; 4-[ 2

-(

2 -Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)-2 cyclohexyl-acetylamino]-benzoic acid methyl ester; 2-(Phenyl-2-ethyl)benzoic acid N-hydroxy amide; 10 4-[ 2

-(

2 -Acylhyrdazinomethyl-4-methyl-pentanoylamino)-3-(1H-indol-3 yl)-propionylamino]-benzoic acid methyl ester; 2-(Propylthio)-pyridine-3-N-(hydroxy)carboxamide; 4-[ 2

-(

2 -Carboxymethyl-5-phenyl-pentanoylamino)-2 cyclohexylacetylamino]benzoic acid methyl ester; 15 [4-(N-Hydroxyamino)-2R-isobutyl-3S-((thien-2-ylthio)methyl)succinyl] L-phenylalanine-N-methylamide; N-Hydroxy-5-phenylpentanamide; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 20 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-4-pentenoyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-4-pentenoyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester, trifluoroacetate salt; 2-(Phenyl-2-ethyl)pyridine-3-N-hydroxycarboxamide; 25 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl 30 valeroyl]aminobenzoic acid methyl ester; 2

-[

3

-(

3 -Hydroxy-phenyl)-propyl]-benzohydroxamic acid; 2-(Thiobenzyl)benzoic acid N-hydroxy amide; 1-( 3 -Phenyl-propyl)-pyrrolidine-2-hydroxamic acid; WO 00/04892 PCT/US99/13948 -122 4

-[

2

-(

2 -Carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[ 2

-(

2 -Carboxymethyl-5-(N'-methylureido)valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 5 4

-[

2

-(

2 -Carboxymethyl-5-(triflouroacetamido)valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[ 2

-(

2 -Carboxymethyl-2-phenylacetylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4

-[

2

-(

2 -Hydroxaminocarbonylmethyl-2-phenylacetylamino)-4-methyl 10 valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl acetylamino]-benzoic acid methyl ester; 2-[3-(3-Amino-phenyl)-propyl]-benzohydroxamic acid; cis-4-Benzyloxy-pyrrolidine-2-carboxylic acid; 15 4-[2-(2-Carboxymethyl-5-(3-amino-4-(trifluoromethyl)phenyl) valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 4

-[

2

-(

2 -Carboxymethyl-5-(methanesulfamido)valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; N-Cbz-L-Tyrosine; 20 N-Boc-L-Tryptophan; 4-[ 2 -(Carboxy- 2 -o-tolyl-propionylamino-4-methyl-pentanoylamino] benzoic acid methyl ester; 4-[ 2 -(Carboxymethyl-hepanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 25 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4

-[

2

-(

2 -Carboxymethyl-5-(4-n-butylphenyl)-4-pentenoyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 4

-[

2

-(

2 -Carboxymethyl-2-(2-thienyl)acetylamino)-4-methyl 30 valeroyl]aminobenzoic acid methyl ester; 4

-[

2

-(

2 -Carboxymethyl-4-(3-aminophenyl)-butyryl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; WO 00/04892 PCT/US99/13948 -123 4-[2-(2-Carboxymethyl-5-(biphen-4-yl)-valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; cis-4-Benzylsulfanyl-pyrrolidine-2-carboxylic acid; 2-Cyclohexylmethyl sulfonyl-benzoic acid; 5 Pyrrolidine- I -carbothioic acid phenethyl-amide; 3-(2-Methyl-thiazol-4-yl)-N-phenethyl-propionamide; N-Phenyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl] propionamide; 3-(3H-Imidazol-4-yl)-N-phenethyl-propionamide; 10 4-[2-(2-Carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 2-Cyclohexylmethyl sulfonyl-benzohydroxamic acid; [2-Oxo-3 -(3 -phenyl-propyl)-tetrahydro-furan-3 -yl] -acetic acid; 4-[ 2 -(2-Carboxymethyl-5-(fluoren-2-yl)valeroyl)amino)-4-methyl 15 valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(3-thienyl)acetylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Benzylthio-3-carboxy-propionylamino)-4-methylpentanoylamino] benzoic acid methyl ester; 20 4 -[2-(2-Carboxymethyl-4-(2-indolyl)butyrylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 1 -Allyl-3-(2-hydroxyethyl)-2-thiourea; 3-(I-Hydroxyimino-propyl)-6-phenyl-hexanoic acid; 2-(3H-Imidazol-4-ylmethyl)-N 1,N 4-diphenethyl-succinamide; 25 3-(2-Hydroxymethyl-3H-imidazol-4-yl)-N-phenethyl-propionamide; 6-Phenyl-3-propionyl-hexanoic acid; 4- { 2-([2-Hydroxyamino-2-hydroxyimino-ethyl] -5-phenyl pentanoylamino)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 4

-[

2

-(

2

-(

2 -Phenylcyclopropyl)succinylamino)-4-methyl 30 valeroyl]aminobenzoic acid methyl ester; 6-Biphenyl-4-yl-[2,2-dimethyl- 1 -(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid trifluoroacetate salt; WO 00/04892 PCT/US99/13948 -124 3-[1-(5,6-Dichloro- 1 H-benzoimidazol-2-yl)-3-methyl-butylcarbamoyl]-5 methyl-hexanoic acid; 6-Biphenyl-4-yl-3-[1-(5,6-dichloro-IH-benzoimidazol-2-yl)-3-methyl butylcarbamoyl]-5-methyl-hexanoic acid; 5 2 -Carboxymethyl-heptanoyl-2-(N-methylcarboxamide)piperidine; 4-[ 2

-(

2

-(

2 -Phenylcyclopropyl)succinylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 2-Carboxymethyl-heptanoyl-3-(N-methylcarboxamide) hexahydropyridazine; 10 6-Biphenyl-4-yl-3-[1-[3-(3-hydroxy-ethyl)-phenylcarbamoyl]-2,2 dimethyl-propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5-methyl 3 S-hexyl)succinamide; 6-Biphenyl-4-yl-3-[I-[3-(2-aminoethyl)-phenylcarbamoyl]-2,2-dimethyl 15 propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl)-N-(diphenylmethyl)succinamide; 2R-(3-(4-Biphenyl)propyl)-N-(phenylmethyl)succinamide; 2

-(

2 -Oxo-imidazolidin-4-ylmethyl)-5-phenyl-pentanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N1-[1-(5,6-dichloro-1H-benzoimidazol-2-yl) 20 3-methyl-butyl]-N4-hydroxy-succinamide hexanoic acid; 6-Biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid, N-hydroxyamide; 2R-(3-(4-Biphenyl)propyl)-N-((1-hydroxy-1-methylethyl)phenylmethyl) succinamide; 25 6-Biphenyl-4-yl-3-[1-phenylcarbamoyl-2-(4-cyano-benzylsulfanyl)-2 methyl-propylcarbamoyl]-hexanoic acid; 4-{ 2-[ 2 -Carboxymethyl-5-(4'-hydroxy-biphenyl-4-yl)-pentanoylamino]-4 methyl-pentanoylamino } -benzoic acid methyl ester; I -(N-Methyl-N-phenethylthiocarbomyl)-pyrrolidine-2-carboxylic acid; 30 6-Biphenyl-4-yl-3-({cyclohexyl-[ 2

-(

4 -sulfanoyl-phenyl)-ethylcarbamoyl] methyl}-carbamoyl)-hexanoic acid; 3R(6-(4-Biphenyl)-3-(N-benzylcarbamoyl))-hexanoic acid N-hydroxyamide; WO 00/04892 PCT/US99/13948 -125 [3-(3-Biphenyl-4-yl-propyl)-2-oxo-pyrrolidin-3-yl]-acetic acid; 2-Benzylsulfonyl-cyclopent- I -ene-carboxylic acid hydroxamide; [2-Oxo-3 -(3 -phenyl-propyl)-pyrrolidin-3-yl]-acetic acid; [3 -(3 -Naphthalen-2-yl-propyl)-2-oxo-pyrrolidin-3-yl] -acetic acid; 5 2-Benzylsulfonyl-cyclohex- 1 -enecarboxylic acid hydroxy amide; 6-Benzylsulfonyl-cyclohex- 1 -enecarboxylic acid hydroxy amide; 2R-(3-(4-Biphenyl)propyl)-N-(3-methylpyridine)succinamide; {3-[3-(3-Hydroxy-phenyl)-propyl]-2-oxo-pyrrolidin-3-yl} -acetic acid; 6-Biphenyl-4-yl- { [cyclohexyl-(3 -morpholin-4-yl-propylcarbamoyl) 10 methyl]-carbamoyl}hexanoic acid; [2-Oxo-3 -(3-biphenyl-propyl)-tetrahydro-furan-3-yl] -acetic acid; 4-[2-(2-Thioamidomethyl-5-phenyl-valerylamino)-4-methyl valeroylamino]-benzoic acid methyl ester; 4-[2-(2-Amino-2-hydroxyimino-ethyl-5-phenyl-valerylamino)-4-methyl 15 valeroylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl- 1 -(4-methylsulfamoyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(2-hydroxyethylsulfamoyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 20 1-(N-Hydroxy)-3-(2-bibenzyl)urea; 4-(2-{ 5-[7-(2-Amino-acetylamino)-9H-fluoren-2-yl]-2-carboxymethyl pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester TFA salt; 3R-(6-(4-Biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-hexanoic acid N-hydroxy amide; 25 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl) phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino-ethylsulfamoyl) phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid, trifluoroacetate salt; 4-(2-{2-Carboxymethyl-5-[4-(1H-tetrazol-5-yl)-phenyl]-pentanoylamino} 30 4-methyl-pentanoylamino)-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-ethyl)-phenyl)-pentanoylamino) 4-methyl-pentanoylamino]-benzoic acid methyl ester; WO 00/04892 PCTIUS99/13948 -126 4-(2-{ [5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3 carbonyl] -amino } -4-methyl-pentanoylamino)benzoic acid methyl ester; 5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3 carboxylic acid(2-cyclohexyl- 1 -methylcarbamoyl-ethyl)amide; 5 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-(3-morpholin-4-yl-sulfamoyl) phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-( 4 -methylsulfanyl-phenylcarbamoyl) propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl- 1 -( 4 -methylsulfonyl-phenylcarbamoyl) 10 propylcarbamoyl]-hexanoic acid; 4

-[

2 -(5-Biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-pent-4 enoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl- 1 -( 4 -methylsulfinyl-phenylcarbamoyl) propylcarbamoyl]-hexanoic acid; 15 4-(2-{[5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3 carbonyl]-amino } -4-methyl-pentanoylamino)benzoic acid methyl ester; 5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3-carboxylic acid(2-cyclohexyl- 1 -methylcarbamoyl-ethyl)amide; 6-Biphenyl-4-yl-[2,2-dimethyl- 1 -(pyridin-4-ylcarbamoyl) 20 propylcarbamoyl]-hexanoic acid; 4-[ 2

-(

2 -Carboxymethyl-5-(4-cyano-biphenyl-4-yl)-pentanoylamino)-4 methyl-pentanoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy- I -(S)-phenyl-ethylcarbamoyl)-hexanoic acid; 25 3-(R)-(1 -(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy- 1 -hydroxymethyl-ethylcarbomyl) hexanoic acid; 4-[ 2

-(

2 -Carboxymethyl-5-(4-pyridin-4-yl-phenyl)-pentanoylamino)-4 30 methyl-pentanoylamino]benzoic acid methyl ester; 6-Biphenyl-4-yl(2-hydroxy-2-methyl- I -phenylcarbamoyl propylcarbamoyl)-hexanoic acid; WO 00/04892 PCTIUS99/13948 -127 6-Biphenyl-4-yl(2-hydroxy-2-methyl- 1 -phenylcarbamoyl propylcarbamoyl)-hexanoic acid; 3-{2-Allylsufamyl-2-methyl-1-[ 2

-(

4 -sulfamoyl-phenyl)-ethylcarbamoyl] propylcarbamoyl}-6-biphenyl-4-yl-hexanoic acid; 5 4-[ 2 -(5-Biphenyl- 4 yl-2-carboxymethyl-pentanoylamino)-4,5-dihydroxy pentanoylamino]-benzoic acid methyl ester; 4-(2-{ 5-[ 4 '-(2-Amino-ethoxy)-biphenyl-4-yl]-2-carboxymethyl pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy-1-(S)-phenyl-ethylcarbamoyl) 10 hexanehydroxamic acid; 3-(R)-(1 -(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl hexanehydroxamic acid; N-[5-(Biphenyl- 4 -yl)- 2 -(N-hydroxyformamido)methylpentanoyl]-tert leucine, N-(pyrid-4-yl)amide; 15 [3-(3-Naphthalen-2-yl-propyl)-2-oxo-tetrahydro-furan-3-yl] -acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy- 1 -hydroxymethyl-ethylcarbomyl) hexanehydroxamic acid; 4-[ 2

-(

2 -Carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4-methyl pentanoylamino]-benzoic acid methyl ester; 20 3-[2,2-Dimethyl-1-(pyridin- 4 -ylcarbamoyl)-propylcarbamoyl]-5-methyl hexanoicacid; NI -[2,2-Dimethyl- 1 -(pyridin-4-ylcarbamoyl)-propyl]-N4-hydroxy-2 isobutyl-succinamide; 4-{2-[ 2 -Carboxymethyl-5-(2-fluoro-biphenyl-4-yl)-pentanoylamino]-4 25 methyl-pentanoylamino}-benzoic acid methyl ester; 6-Biphenyl-4-yl-3(R)-(1 (S)-hyroxymethyl-2,2-dimethyl propylcarbamoyl)-hexanoic acid; 4-{2-[5-Biphen-4-yl-2-(1-carboxy-ethylamino)-pentanoylamino]-4 methyl-pentanoylamino}-benzoic acid methyl ester; 30 6-Biphenyl-4-yl-3(R)-(1 (S)-hyroxymethyl-2,2-dimethyl propylcarbamoyl)-hexanehydroxamic acid; WO 00/04892 PCT/US99/13948 -128 6-Biphenyl-4-yl-3-[2,2-dimethyl- I -( 4 -methylsulfinyl-phenylcarbamoyl) propylcarbamoyl]-hexanoic acid; 2-(Biphenyl-4-ylsulfonyl)-cyclohex- 1 -enecarboxylic acid hydroxyamide; 6-(Biphenyl-4-ylsulfonyl)-cyclohex- 1 -enecarboxylic acid hydroxyamide; 5 2-Phenethylsulfanyl-cyclohex- I -enecarboxylic acid hydroxyamide; 6-(4'-cyano-biphenyl-4-yl)-3-[2-hydroxy-1-(4-methylsulfinyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1-{1-[i-( 4 -Methoxycarbonyl-phenylcarbamoyl)-3-methyl butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid; 10 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-( 4 S-methylsulfinyl-phenylcarbamoyl) propylcarbamoyl]-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-3,3,3-trifluoropropyl)-phenyl) pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 2 -Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 15 1-{ 1 -(4-Methoxycarbonyl-phenylcarbamoyl)-3 -methyl butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid; trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 4-[2-(2-Carboxymethyl-5-(4-(2-methylthiazol-4 yl)phenyl)valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 20 1-{1-[i-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl butylcarbamoyl]-3-methyl-butylthiocarbamoyl}-pyrrolidine-2-carboxylic acid; 3-[(Cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl) methyl)-carbamoyl]-6-(4-pyridin-4-yl-phenyl)-hexanoic acid trifluoroacetate salt; trans- 2 -(Biphenyl-4-yl-methylsulfanyl)-cyclohexancarboxylic acid 25 hydroxamide; 6-Biphenyl-4-yl-3 -(1 -hydroxymethyl-2,2-dimethyl-but-3-enylcarbamoyl) hexanoic acid; 6-Biphenyl-4-yl-3-(1 -hydroxymethyl-2,2-dimethyl-but-3-enylcarbamoyl) hexanoic acid; 30 6-Biphenyl-4-yl-3-(R)-(1 -hydroxymethyl-2-(S)-(1 H-imidazol-4-yl) ethylcarbamoyl)-hexanoic acid; WO 00/04892 PCTIUS99/13948 -129 3-(R)-(2-(R)-Benzyloxy- I -(S)-hydroxymethyl-propylcarbamoyl)-6 biphenyl-4-yl-hexanoic acid; 4

-[

4 -Methyl-2-(2-nitromethyl-5-phenyl-pentanoylamino) pentanoylamino]-benzoic acid methyl ester; 5 6-Biphenyl-4-yl-3-[3-methyl-1-(4-(2-hydroxyethylsulfamoyl) phenylcarbamoyl)-butylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-(1 -hydroxymethyl-2-phenyl-ethylcarbamoyl)-hexanoic acid; Ni -(1 -Benzyl-2-hydroxy-ethyl)-2-(3-biphenyl-4-yl-propyl)-N4-hydroxy 10 succinamide; 6-Biphenyl-4-yl-3-(R)-(1 -hydroxymethyl-2-(S)-(1 H-imidazol-4-yl) ethylcarbamoyl)-hexanehydroxamic acid; N-Hydroxy-2-[2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl] acetamide; 15 4-[ 2

-(

2 -Carboxymethyl-5-(2-hydroxy-biphen-4-yl)-valeroylamino)-4 methyl-valeroylamino]-benzoic acid methyl ester; N1-(2-Benzyloxy-1-hydroxymethyl-propyl)-2-(3-biphenyl-4-yl-propyl)

N

4 -hydroxy-succinamide; trans- 2

-(

4 -Phenoxy-benzylsulfanyl)-cyclohexancarboxylic acid 20 hydroxamide; 2-(4-Indol- 1 -yl-benzylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 6-Biphenyl-4-yl-3-[2-hydroxy-2-methyl- 1 -(4S-methylsulfinyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6 -Biphenyl- 4 -yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3 25 ylcarbamoyl)-hexanoic acid; 5-Biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoic acid{ 1-[4

(

2 -dimethylamino-ethylsulfamoyl)-phenylcarbamoyl]-3-methyl-butyl}-amide; 2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-N I -(2,4,5-trihydroxy-6 hydroxymethyl-tetrahydro-pyran-3-yl)-succinamide; 30 6 -Biphenyl- 4 -yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3 ylcarbamoyl)-hexanoic acid; WO 00/04892 PCT/US99/13948 -130 N-[2,2-Dimethyl- 1 S-(pyridin-4-ylcarbamoyl)-propyl]-3R-thiophen-3-yl succinamic acid; 4-[2S-(2R-(3-Biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-propionylamido)-4 methyl-pentanoylamino]-benzoic acid methyl ester; 5 3-(R)-(2-Benzyloxy-phenyl)- 1 -(S)-hydroxymethyl-ethylcarbamoyl)-6 biphenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy- I -(S)-(4-hydroxy-benzyl) ethylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid; 10 N-[ 2

-(

3

-(

4 -biphenyl)propyl)-5,5-difluoro-4-oxopentanoyl)-L-t-leucine,

N'

4-(methylthio)phenyl amide; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-1-(S)-(4-hydroxy-benzyl) ethylcarbamoyl)-hexanehydroxamic acid; 4-{2-[ 2 -carboxymethyl-5-(4'-sulfamoyl-biphenyl-4-yl)-pentanoylamino] 15 4-methyl-pentanoylamino}-benzoic acid methyl ester; 2

-(

2 -Biphenyl-4-yl-ethylsulfanyl)-cyclohexane carboxylic acid hydroxyamide; 3-Acetyl-6-biphenyl-4-yl-3-hexanoic acid; N-[5-(Biphen-4-yl)-2-(I-carboxy-2-hydroxybut-1-yl)pentanoyl]-t-L 20 leucine, N'-(4-methylthiophenyl)amide; 6-Biphenyl-4-yl-3-( 2 -hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N 4 -hydroxy-NI-(2-hydroxy-cyclohexyl) succinamide; 6-Biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid hydroxamide; 25 6 -Biphenyl- 4 -yl- 3

-(

2 -Hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid ethyl ester; 2-(3-Biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3-phenyl-prop 2-yl)-propionamide; 30 N-[5-(Biphen-4-yl)-2-(1 -carboxy-2-hydroxyethyl)pentanoyl]-L-t-leucine, N'-(4-methylthiophenyl)amide; WO 00/04892 PCT/US99/13948 -131 3-(R)-(2-Hydroxy- 1 -(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2 methyl-thiazol-4-yl)-phenyl)-hexanoic acid; 3-(R)-(2-Hydroxy-1-(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2 methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid; 5 5-Biphenyl-4-yl-2-(1 -hydroxymethyl-3-methylsulfanyl-propylcarbamoyl) pentanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N-hydroxy-N'-(I -hydroxymethyl-3 methylsulfanyl-propyl)malonamide; 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-1-carbonyl)-hexanoic acid; 10 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine- I -carbonyl)-hexanoic acidhydroxyamide;

I-(

4 -Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 1-[ 4 -Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid 15 hydroxyamide; N-(1 -Benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-yl-pyrrol- I -yl)-succinamic acid; N-(1 -Benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-yl-pyrrol- I -yl)-succinamic hydroxamic acid; 20 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(1(S)-hydroxymethyl-2,2-dimethyl propylcarbamoyl)-hexanoic acid; 3-(1-Benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid; NI -(1 -benzyl-2-hydroxy-ethyl)-N 4 -hydroxy-2-isobutyl-succinamide; 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(l (S)-hydroxymethyl-2,2-dimethyl 25 propylcarbamoyl)-hexanoic hydroxamic acid; 1-[ 4 -Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; 6-Biphenyl-4-yl-3-(2-hydroxy-1-hydroxmethyl-propylcarbamoyl) hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-cyclohexyl- I -(S)-carbamoyl)-hexanoic acid; 30 6-Biphenyl-4-yl-3-(2-hydroxy-I-hydroxmethyl-propylcarbamoyl) hexanoichydroxamic acid; WO 00/04892 PCT/US99/13948 -132 2S-[(1 S-Benzyl-2-hydroxyethylcarbamoyl)-3R-biphenyl-4-yl-pyrrol-1-yl methyl]-pentanoic acid; 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-(2R-hydroxy-cyclohexyl-1R-yl) succinamic acid; 5 2-(3-Biphenyl-4-yl-pyrrol-1-yl)-3-carboxamate-N-(I-hydroxy-3-phenyl prop-2-yl)-propionamide; trans- 2

-(

3 -Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid; trans- 2 -(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acidhydroxyamide; 10 6-Biphenyl-4-yl-3-(R)-(1-(S)-hydroxymethyl-2-(3-pyridyl) ethylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-2-(S)-hydroxy-3-(R)-(1-hydroxymethyl-2-(S)-(1H imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid; 1-[ 4 -Biphenyl- 4 -yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; 15 1-[ 4 -Biphenyl- 4 -yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; 1-( 4 -Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; 6-Biphenyl-4-yl-2S-hydroxy-3R-(I S-hydroxymethyl-3-methylsulfanyl propylcarbamoyl)-hexanoic acid; 20 6-Biphenyl-4-yl-3-(R)-(1 -(S)-hydroxymethyl-2-(3-pyridyl) ethylcarbamoyl)-hexanehydroxamic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R-(1 S-hydroxymethyl-3-methylsulfanyl propylcarbamoyl)-hexanoic hydroxamic acid; 1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]- 4 -(tert-butoxycarbonyl) 25 piperazine-2-carboxylic acidhydroxyamide; 1-[ 4

-(

4 -Bromo-phenoxy)-benzenesulfonyl]-piperazine-2-carboxylic acidhydroxyamide; 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-[2-hydroxy-1 S-(1H-imidazol-4-yl methyl)-ethyl]-succinamic acid trifluoroacetate; 30 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-[1 S-(methoxy-methylcarbamoyl)-3 methyl-butyl]-succinamic acid; N-(I-Acetyl-3-methyl-butyl)-3-(3-biphenyl-4-yl-pyrrol-1-yl)-succinamic acid; WO 00/04892 PCT/US99/13948 -133 6-Biphenyl-4-yl-3-(R)-(2-oxo- I -tetrahydrofuran-3-(S)-ylcarbamoyl) hexanoic acid; 3-[2,2-Dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-2-hydroxy 5-methyl-hexanoic acid-hydrochloride salt; 5 N 4 -(2,2-Dimethyl-I -methylcarbamoyl-propyl)-2,N1-dihydroxy-3 isobutyl-succinamide; 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanoic acid; N-(1-Benzyl-2-hydroxy-ethyl)-3-( 4 -biphenyl-4-yl-pyrazol-1-yl) succinamic acid; 10 N-(8-Oxo-4-oxa-1,7-diaza-tricyclof9.6.1.0 12,17]octadeca 11(18),12(17),13,15-tetraen-9R-yl)-3S-(3-phenyl-pyrrol-1-yl)-succinamic acid; 4-Acetyl- I -[ 4 -phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxyamide; I -(Diphenylphosphinic)-piperidine-2-carboxylic acid hydroxamide; 15 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-[3S-(2RS-hydroxy-5-methyl)-hexyl] succinamic acid; N-(1 -(S)-Benzyl-2-hydroxy-ethyl)-3-(R)-(2-biphenyl-4-yl cyclopropylmethyl)-succinamic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-1-tetrahydrofuran-3-(S)-ylcarbamoyl) 20 hexanehydroxamic acid; 1-[ 4

-(

4 -Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2 carboxylic acid N-hydroxyamide; 4-(4-Methoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 25 3-(Diphenylphosphinic)-propanoic acid; 3-(Diphenylphosphinic)-propanoic acid hydroxyamide; 4-[2-(2-Carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl) pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 1-[ 4 -(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-4-(N 30 methylcarbamoyl)piperazine-2-carboxamide; 4

-[

4 -(4-Bromo-phenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxyamide; WO 00/04892 PCT/US99/13948 -134 3-(3-Biphenyl-4-yl-pyrrol- 1 -yl)-N-(2,2-dimethyl- 1 -methylcarbamoyl propyl)-succinamic acid; 1-[ 4 -Phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxyamide; 5 4[4-Phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxyamide; 3-[2-Biphenyl-4-yl-ethylsulfanyl]-tetrahydro-pyran--4-carboxylic acid N-hydroxyamide; 6-Biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid; 10 1-[ 4

-(

4 -Bromo-phenoxy)-benzenesulfonyl]piperdine-2-amidoxime; 2-(3-Biphenylnitrile-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3-phenyl prop-2-yl)-propionamide; {3-[3-(3-Amino-phenyl)-propyl]-2-oxo-tetrahydro-furan-3-yl } -acetic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid; 15 5-Biphenylvaleric acid; 1-[ 4 -(Methoxy)-benzenesulfonyl]piperdine-2-amidoxime; 1-[ 4 -Phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxyamide; { 3-(3-(3-Methylamino-phenyl)-propyl)-2-oxo-tetrahydro-furan-3-yl} 20 acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl) hexanehydroxamic acid; 4-(1H-Indole-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide; 25 1 R-[ 4 -Bromo-phenoxy)-benzenesulfonyl)-N-amino-piperidine-2 carboxamide; 2-(3-Biphenyl-4-yl-propyl)-3, N-4-dihydroxy-N I-(1 (S)-hydroxymethyl-3 methanesulfinyl-propyl)-succinamide; N-(1 -Benzyl-2-hydroxy-ethyl)-3-[3-( 4 '-carbamoyl-biphenyl-4-yl)-pyrrol 30 1-yl]-succinamic acid; 1-(Methyl-phenylphosphinic)-piperidine-2-(R)-carboxylic acid hydroxamide; WO 00/04892 PCTIUS99/13948 -135 4

-(

4

-(

4 -Chlorophenoxy)benzenesulfonyl)-N-hydroxy-morpholine-3R carboxamide; 2S-[ 1 R-(3-(4'-Cyano-biphenyl-4-yl)-pyrrol- I -yl)-N-(2,2-dimethyl-

IS

hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid; 5 2(S,R)-{ 1S-Benzyl-2-hydroxyethylcarbamoyl-[3R-(4'-cyano-biphenyl-4 yl)-pyrrol-1-yl]-methyl}pentanoic acid; 2S-[3-(Biphenyl-4-yl)-pyrrol-IR-yl-(1S-hydroxymethyl-2,2-dimethyl propylcarbamoyl)-methyl]-5-hydroxypentanoic acid; 1-(1,3-Dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acid 10 hydroxamide; 3-[3-(4'-Carbamoyl-biphenyl-4-yl]-pyrrol-1-yl)-N-(1-hydroxymethyl-2,2 dimethyl-propyl)-succinamic acid; 4-Methyl-I -( 4

-(

4 -chlorophenyl)benzenesulfonyl)-N-hydroxy-2R piperazinecarboxamide hydrochloride; 15 1-[ 4 -Chlorophenoxybenzenesulfonyl]-N-hydroxy-2R piperazinecarboxamide; 2

-(

3 -Phenyl-propylsulfonyl)-cyclohexane carboxylic acid hydroxamide; 1 -(Pyrolidine- I -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; I -(Piperidine- I -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 20 4

-[

4 -Bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid-N-hydroxyamide; 1-[ 4

-(

4 -Methoxy-phenylsulfanyl)-benzenesulfonyl]-piperdine-2-carboxylic acid hydroxyamide; 1-[ 4

-(

4 -Nitrile-phenoxy)-benzenesulfonyl]-4-(tert-butoxycarbonyl) 25 piperazine-2-carboxylic acid N-hydroxyamide; 2S-[3-(Biphenyl-4-yl)-pyrrol-1R-yl-(1 S-hydroxymethyl-2,2-dimethyl propylcarbamoyl)-methyl]-pent-4-enoic acid; 6-Oxo-3-( 4 -phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4 carboxylic acid hydroxamate; 30 4-(t-Butoxycabonyl)- I -( 4 -(pyridin- 2 -yl)oxybenzensulfonyl)-N-hydroxy piperazine-2-carboxamide; WO 00/04892 PCT/US99/13948 -136 4-[(4-Fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid-N-hydroxyamide; 4-[4-(Fluoro-phenoxy)-benzenesulfonyl]-oxothiomorpholine-3-carboxylic acid-N-hydroxyamide; 5 N-(2,2-Dimethyl- 1 S-hydroxymethyl-propyl)-3R-[3-(4-pyridin-4-yl phenyl)-pyrrol-1-yl]-succinamic acid; N-(1 S-Benzyl-2-hydroxy-ethyl)-3S-(5-biphenyl-4-yl-furan-2-yl) succinamic acid; 4

-(

4 -Butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acid 10 hydroxyamide; 4-(4-Butoxy-benzenesulfonyl)- 1 -oxothiomorpholine-3-carboxylic acid hydroxyamide; 1-[4-(4-Fluorophenyl)benzenesulfonyl]-4-(tert-butoxycarboxyl)-2R piperazine-2-carboxylic acid hydroxyamide; 15 1-((4-(4-Chlorophenyl)-piperazine)- 1 -sulfonyl)-piperidine-2-carboxylic acid hydroxamide; cis- 2 -Phenethylsulfanyl-cyclohexanecarboxylic acid hydroxyamide; N-(2-Hydroxy- 1 S-phenyl-ethyl)-3R-[3-( 4 -pyridin-4-yl-phenyl)-pyrrol- 1 yl]-succinamic acid; 20 1-[4-(4-Fluorophenyl)benzenesulfonyl)-N-hydroxy-2R piperazinecarboxamide hydrochoride; 1-(Diphenylphosphinic)-pyrolidine-2-(R)-carboxylic acid-hydroxyamide; N,N-{(Diphenylphosphinic)-(acetic acid-sodium salt)} -hydrazide; N-(1 -Benzyl-2-hydroxy-ethyl)-3 -(1 -biphenyl-4-yl- 1 H-pyrrol-3-yl) 25 succinamic acid; trans- 2 -Phenethylsulfonyl-cyclohexanecarboxylic acid hydroxyamide; 1-[4-(4-Fluorophenyl)-piperazine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxamide; 1-[ 4

-(

4 -Fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylic 30 acid hydroxyamide; 4

-[

4 -(Bromo-phenoxy)-benzenesulfonyl]-2,2-dimethyl- I -oxo thiomorpholine-3-carboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -137 N-(2,2-Dimethyl- 1 S-methylcarbamoyl-propyl)-3R-(3-phenyl-pyrrol- 1-yl) succinamic acid; 3R-(3-Biphenyl-4-yl)-N-(2-hydroxy- I S-hydroxymethyl-2-methyl-propyl) succinamic acid; 5 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acid; 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acid hyroxyamide; I -Phenethylcarbamoyl-pyrrolidine-2(R)-carboxylic acid; R-4-[4-(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo thiomorpholine-3-carboxylic acid hydroxyamide; 10 4-(Ethoxycarbonyl)methyl- 1 -( 4

-(

4 -chlorophenyl)benzenesulfonyl)-N hydroxy-2R-piperazinecarboxamide hydrochloride; N-(2R-Hydroxy-indan-1R-yl)-3R-[3-( 4 -pyridin-4-yl-phenyl)-pyrrol-1 -yl] succinamic acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[3-(4-pyridin-4-yl 15 phenyl)-pyrrol-1-yl]-succinamic acid; N-(2,2-Dimethyl-IS-methylcarbamoyl-propyl)-3R-[3-(4-pyridin-4-yl phenyl-4-yl)-pyrrol-1-yl]-succinamic acid; I -Phenethylcarbamoyl-pyrrolidine-2-(R)-carboxylic acid hydroxyamide; N-(2,2-Dimethyl-1S-methyl carbamoyl-propyl)-3R-[3-(4-propyl-phenyl) 20 pyrrol-1-yl]-succinamic acid; 1-(4-Benzyl-piperazine- I -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 3(S)-N-hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl tetrahydro-2H- 1,4-thiazine-3-carboxamide; 25 2(R)-4-Methyl- I -( 4

-(

4 -fluorophenyl)benzenesulfonyl)-N-hydroxy piperazine-2-carboxamide; N-(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-3 -(5-biphenyl-4-yl-furan-2 yl)-succinamic acid; N-(2,2-Dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-pyridin-4-yl-pyrrol 30 1 -yl)-succinamic acid; 1-((2-Pyridyl)-4-piperazine- I -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -138 1-[ 4 -(Pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperdine-2-carboxylic acid hydroxyamide; N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine; N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; 5 N-(8-oxo-4-oxa-1,7-tricyclo[9.6.1.0 12,17]octadeca-11(18),12(17),13,15 tetraen-9-yl)-3-[4-(4-pyridyl)-3-phenyl-pyrrol-1-yl)-succinamic acid; 3-[3-(4-Pyridyl)phenyl-4-yl-pyrrol-I -yl]-N-[2,2-dimethyl-1-(4 pyridyl)carbamoyl-propyl]-succinamic acid; 2,2-Dimethyl-4-[4-(pyridin-2-yloxy)-benzenesulfonyl]-thio-morpholine-3 10 carboxylic acid hydroxyamide;

N-[

4

-(

4 -Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine;

N-[

4

-(

4 -Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; 2-[ 2 -(N'-Acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl-pentanoic acid; 15 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl tetrahydro-2H- 1,4-thiazine-3 -carboxamide hydrochloride; 2-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-butyric acid; 2-[ 4

-(

4 -Chloro-phenoxy)-benzenesulfonylamino)-N-hydroxy-3,3 20 dimethyl-butyramide; 3(R)-N-Hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2-dimethyl tetrahydro-2H- 1,4-thiazine-3-carboxamide; N-(4-Phenoxy-benzenesulfonyl)-3, 3 -dimethyl-S-(benzylthio)-D-cysteine; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D-cysteine, 25 N-hydroxyamide; 2-[4-(Pyridin-2-yl-oxy)-benzenesulfonylamino]-3,3-dimethyl butyric acid; 2

-[

4 -(Pyridin-2-yl-oxy)-benzenesulfonylamino]-N-hydroxy-3,3-dimethyl butyramide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine; 30 3-[3-(4'-Carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-1 methylcarbamoyl-propyl)-succinamic acid; WO 00/04892 PCT/US99/13948 -139 3-[3-(4'-Cyano-biphenyl-4-yl)-pyrrol- I -y]-N-(2,2-dimethyl- 1 methylcarbamoyl-propyl)-succinamic acid; 2

-(

2 -Biphenyl-4-yl-ethylsulfonyl)-cyclohex- I -ene-carboxylic acid hydroxyamide; 5 6-(2-Biphenyl-4-yl-ethyl sufonyl)-cyclohex- 1 -ene-carboxylic acid hydroxyamide; N-(4-Pyridin-4-yl-oxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D cysteine; 3-[3-4'-Carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-[2,2-dimethyl-1 10 (pyridin-4-yl-carbamoyl)-propyl]-succinamic acid; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine, N-hydroxyamide; 1-(4-Phenoxy-piperdine-1-sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 15 3(R)- 4

-[

4

-(

4 -Bromo)phenoxybenzenesulfonyl]-2,2-dimethyl-tetrahydro 2H-1,4-thiazine-3-carboxylic acid; N-(4-[4-Chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylthio) D-cysteine; N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylthio) 20 D-cysteine, N-hydroxyamide; N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S (methylsulfoxy)-D-cysteine, N-hydroxyamide; 2(R)-[ 4 -(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin 2-ylsulfanyl)-butyric acid; 25 2

(R)-[

4

-(

4 -Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin 3-ylsulfanyl)-butyric acid; 2(R)-[ 4 -(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridin 4-ylsulfanyl)-butyric acid; cis- 2

-(

2 -Phenyl-ethanesulfonyl)-cycloheaxanecarboxylic acid 30 hydroxyamide; 3(R)-N-Hydroxy-4-(4-(imidaz- I -yl)phenoxybenzenesulfonyl)-2,2 dimethyl-tetrahydro-2H- 1,4-thiazine-3-carboxamide; WO 00/04892 PCT/US99/13948 -140 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl tetrahydro-2H- 1,4-thiazine-3-carboxamide; 4-[ 2

-(

2 -Hydroxycabamoylmethyl-5-phenyl-pentanoylamino)-4-methyl pentanoyl-benzoic acid methyl ester; 5 trans-2-(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxyamide; 3,3-Dimethyl- 2 -(4-phenoxy-phenylsulfanylmethyl)-butyric acid; 2-[4-(4-Chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin 2-ylmethylsulfanyl)-butyric acid; 10 3R-[3-(4'-Cyano-biphenyl-4-yl)pyrrol-1-yl]-N-[2,2-dimethyl-l S-(pyridin 4 -ylcarbamoyl)-propyl]-succinamic acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid, N-hydroxyamide; N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-3-[I-(4-fluorophenyl)-1H 15 pyrrol-3-yl]-succinamic acid; 2

(R)-[

4

-(

4 -Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(pyridi-n 2-ylsulfanyl)-butyric acid; 2

-(

2 -Biphenyl- 4 -yl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamate; 20 2

-[

4 -(4-Chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin 2 -ylmethylsulfanyl)-butyric acid, N-hydroxyamide; 3, 3 -Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid, N-hydroxyamide; 25 3 -tert-Butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro phenoxy)benzenesulfonylamino)-3-methyl-butyric acid; 1-(4-Phenylsulfanyl-piperidine- 1 -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 1-[ 4

-(

4 -Fluoro-phenoxy)-benzenesulfonyl]-3,3-dimethyl-5-oxo 30 piperazine-2-carboxylic acid; N-(4-[4-Fluorophenoxy]-benzenesulfonylamino)-3-methyl-3-(1 -benzyl imidazole-2-yl-sulfanyl)-butyric acid; WO 00/04892 PCTIUS99/13948 -141 2(R)-[4-(4-Fluoro-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n 2-yl-sulfanyl)-butyric acid, hydroxyamide; 3(R)-N-Hydroxy-4-(4-((pyridin-4-yl)methyl)oxybenzenesulfonyl)-2,2 dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 5 1-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-4-(1-methyl-IH-imidazole-4 sulfonyl)-piperazine-2-carboxylic acid hydroxamide; N-(2,2-Dimethyl-I S-methylcarbamoyl-propyl)-3R-[1-(4'-cyanobiphenyl 4-yl)-I H-pyrrol-3-yl]-succinamic acid; 3-Carboxymethylsulfanyl-2-(4-(4-fluoro-phenoxy) 10 benzenesulfonylamino)-3-methyl-butyric acid; 2,2-Dimethyl-1-oxo- 4

-[

4 -(pyridin-4yloxy)-benzenesulfonyl]-iS14 thiomorpholine-3-carboxylic acid hydroamide; 1-[4-(Pyridin-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylic acid hydroxyamide; 15 2(R)-[4-(4-(fur-3-yl)-phenoxy)-benzenesulfonylamino]-3-methyl-3 (pyridi-n-yl-sulfanyl)-butyric acid; 2

,

2 -Dimethyl-1-oxo-4-[4-(pyridin-4yloxy)-benzenesulfonyl]-S 14 thiomorpholine-3-carboxylic acid hydroamide; {2-[ 4

-(

4 -Fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl 20 1,1 -dimethyl-ethylsulfanyl}-acetic acid tert-butyl ester; 1-[4-(Pyridin-4-ylsulfanyl)-piperidine- 1 -sulfonyl]-piperidine-2-carboxylic acid hydroxyamide; 2(R)-[ 4

-(

4 -Bromo-phenoxy)benzenesulfonylamino]-3-methyl-3 -(pyridi-n yl-sulfanyl)-butyric acid, hydroxyamide; 25 trans- 2

-(

2 -Biphenyl-4-yl-ethylsulfanyl)-cyclohexanecarboxylic acid hydroxyamide; N-[1S-(1H-Imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-yl-phenyl) pyrrol-1 -yl]-succinamic acid formate; N-Methyl-3-[3-( 4 -pyridin-4-yl-phenyl)-pyrrol- I-yl]-succinamic acid; 30 N(4)-(2,2-Dimethyl-1S-hydroxymethyl-propyl)-N(I)-hydroxy-3R-[3-(4 pyridin-4-yl-phenyl)-pyrrol- I-yl] -succindiamide; WO 00/04892 PCT/US99/13948 -142

{

2

-[

4

-(

4 -Fluoro-phenoxy)-benzenesulfonylamino]-2-hydroxycarbamoyl 1,1 -dimethyl-ethylsulfanyl } -acetic acid; 1-[4[(4-Fluoro-phenoxy)-benzenesulfonyl)]-3,3-dimethyl -5-oxo piperazine-2-carboxylic acid hydroxyamide; 5 N-(4-[4-Bromophenoxy]-benzenesulfonylamino)-3-methyl-3-(1 -benzyl imidazole-2-yl-sulfanyl)-butyric acid; 3R-[3-( 4 '-Cyanobiphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-I

S

hydroxymethyl-propyl)-succinamic acid; 2-(R)-[ 4 -(4-Iodophenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-2 10 yl-sulfanyl)-butyric acid; O 3R-[3-(4-Cyano-phenyl)-pyrrol- I -yl]-N-(2,2-dimethyl- I S-hydroxymethyl propyl)-succinamic acid; 2(R)-[ 4

-(

4 -Iodo-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n-yl 15 sulfonyl)butyric acid, hydroxyamide; 2(R)-[ 4

-(

4 -Nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n yl-sulfonyl)butyric acid; 2-[ 4

-(

4 -Fluoro-phenoxy)-benzene sulfonylamino]-3,3-dimethyl-pent-4 enoic acid; 20 2-[ 4

-(

4 -Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl isoxazole-3-ylmethylsulfanyl)-butyric acid; 2

-[

4 -(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5-methyl isoazole-3-ylmethylsulfanyl)-butyric acid; 2-[ 4

-(

4 -Fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3 25 (5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2-[ 4

-(

4 -Bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3 (5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2

-[

4

-(

4 -Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3 (carbomethoxyethylsulfanyl)-butyric acid; 30 1-[ 2 -(Benzothiazol-2-ylsulfanyl)-piperidine-I -sulfonyl]-piperidine-2 carboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -143 3R-[3-(4-Cyano-phenyl)-pyrrol- 1-yl]-N-(2,2-dimethyl- IS methylcarbamoyl-propyl)-succinamic acid; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3 (hydroxyethylsulfanyl)-butyric acid; 5 [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl-sulfanyl) butyric acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[1-(4'-cyanobiphenyl 4-yl)-1H-pyrrol-3-yl]-succinamic acid; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3 10 (amidoethylsulfanyl)-butyric acid; [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-ylsulfanyl) butyric acid; 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5-phenyl pent-4-enoic acid; 15 5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-4,5,6,7-tetrahydro-3H imidazole[4,5,-c]pyridine-6-carboxylic acid hydroxyamide 2 (R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n yl-sulfonyl)butyric acid; 3(S)- 4

-(

4 -((Pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H 20 1,4-thiazine-3-carboxylic acid; 1-[4-(Pyridin-4-ylsulfanyl)-piperidine- I -sulfanyl]-piperidine-2-carboxylic acid hydroxyamide; N- [1 -(LH-imidazol-2-yl)-3-methyl-butyl]-3-[1-(4'-cyanobiphenyl-4-yl) 1 H-pyrrol-3-yl]-succinamic acid; 25 3R-{ 3-[(4-Cyano-phenyl)-acetyl]-pyrrol-I -yl} -N-(2,2-dimethyl- IS methylcarbamoyl-propyl)-succinamic acid; 1-[4-(4-Methoxy-phenylsulfamyl)-piperidine- 1 -sulfonyl]-piperidine-2 carboxylic acid hydroxamide; 3R-[3-(4-Cyano-phenyl)-pyrrol-1-yl]-N-(2,2-dimethyl-iS 30 methylcarbamoyl-propyl)-succinamic acid methyl ester; 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyridi-n yl-sulfonyl)butyric acid, hydroxyamide; WO 00/04892 PCT/US99/13948 -144 1-[4-(4-Methyl-phenylsulfamyl)-piperidine- I -sulfonyl]-piperidine-2 carboxylic acid hydroxamide; 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3 carboxylic acid; 5 4-4(-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3 carboxylic acid hydroxyamide; 4

-[

4

-(

4 -Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine 3-carboxylic acid; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine 10 3-carboxylic acid hydroxyamide; 2(R)-[4-(4-bromo-phenoxy)benzenesulfoxylamino]-3-methyl-3-(pyridi-n yl-sulfuroxide)butyric acid, hydroxyamide; 4-(4-Methoxy-bezensulfonyl)-2,2-dimethyl- 1 -oxo-thiomorpholine-3 carboxylic acid hydroxyamide; 15 2

,

2 -Dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]thiomorpholin-3-ol; 4 -[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethoxy- I -oxo thiomorpholine-3-carboxylic acid hydroxyamide; 2-(R)-3-Methyl-3-(pyridin- 2 -yl-sulfanyl)-[4-(4-trifluoromethylphenoxy) benzenesulfonylamino]-butyric acid; 20 3(R)- 4

-(

4 -(Pyridin- 4 -yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H 1,4-thiazine-3-carboxamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-yl oxy)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4 25 (pyridin-4-yl-oxy)-benzenesulfonylamino]-butyramide; 2R-[ 4

-(

4 -Bromophenoxy)-benzenesulfonylamino]-3-hydroxy-3-methyl butyric acid; 3(S)-2,2-Dimethyl-4-[ 4 -(pyridin- 4 -ylsulfanyl)-benzenesulfonyl] thiomorpholine-3-carboxylic acid hydroxyamide; 30 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4-(pyridin-4-yl sulfanyl)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4 (pyridin-4-yl-sulfanyl)-benzenesulfonylamino]-butyramide; WO 00/04892 PCTIUS99/13948 -145 3,3-Dimethyl-2R-[4-(pyridin-4-ylsulfanyl)-piperidine- I -sulfonylamino] butyric acid; 3,3-Dimethyl-N-hydroxy-2R-[ 4 -(pyridin-4-ylsulfanyl)-piperidine-1 sulfonylamino]-butyramide; 5 2

R-[

4

-(

4 -Bromophenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3 [(1 -methyl-imidazol-2-yl)methylsulfanyl]-butyramide; 2R-[ 4

-(

4 -Bromophenoxy)-benzenesulfonylamino]-3-methyl-3-[(1-methyl imidazol-2-yl)methylsulfanyl]-butyric acid; N-Hydroxy-2-[( 4 -methylbenzenesulfonyl)amino]acetamide; 10 1-[4-(4-Imidazol-I-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2 carboxylic acid hydroxyamide; 1-[4-(4-Imidazol-1-yl-phenylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2 carboxylic acid hydroxyamide; 2(R)-[ 4

-(

4 -Chloro-benzoyl)-cyclohexanesulfonyl]-piperidine- I -carboxylic 15 acid hydroxyamide; I (R)-[4-(4-Chloro-benzoyl)-piperidine-I -sulfonyl]-piperidine-2-carboxylic acid amide; 1 (R)-(4-Pyridin-2-yl-piperazine- I -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 20 1(R)-[4-(4-Imidazol-I -yl-phenoxy)-piperidine- 1 -sulfonyl]-piperidine-2 carboxylic acid; I(R)-[4-(4-Imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]- piperidine-2 carboxylic acid hydroxyamide; N-Hydroxy-3,3-dimethyl-2R-[ 4 -(morpholine-4-carbonyl)piperidine-1 25 sulfonylamino]butyramide; N-Hydroxy-3-methyl-3-(5-methyl-isoxazol-3-yl-methylsulfanyl)-2R-[4 (pyridin-4-ylsulfanyl)-piperidine-sulfonylamino]-butyramide; 4-(4'-Chloro-biphenyl-4-yl)-2RS-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl) ethyl]-4-oxo-butyric acid; 30 4-(4'-Chloro-biphenyl-4-yl)-2R-[2-(1,3-dioxo- 1,3-dihydro-isoindol-2-yl) ethyl]-4-oxo-butyric acid; WO 00/04892 PCT/US99/13948 -146 N-Hydroxy-2R-[4-(4-imidazol- 1 -yl-phenoxy)-piperidine- I sulfonylamino]-3,3-dimethyl-butyramide; 2R-[4-(4-Chloro-benzoyl)-piperazine- 1 -sulfonylamino]-N-hydroxy-3 methyl-3-methylsulfanyl-butyramide; 5 N-Hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4-ylsulfanyl) piperidine- I -sulfonylamino]-butyramide; 4-(Pyridin-4-yloxy)benzenesulfonic acid; 4-(Pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride; (3S)-2,2-Dimethyl-3-thiomorpholine carboxylic acid; 10 3 (R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl 1,1-dioxo-tetrahydro-2H-1,4-thiazine-3-carboxamide; IR-3S-2,2-Dimethyl-1-oxo- 4

-[

4 -(pyridin-4-yloxy)-benzenesulfonyl]-1 thiomorpholine-3-carboxylic acid amide; 1 S-3S-2,2-Dimethyl-1-oxo- 4

-[

4 -(pyridin-4-yloxy)-benzenesulfonyl]-1 15 thiomorpholine-3-carboxylic acid amide; and 4-[4-(1 -Hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl thiomorpholine-3-carboxylic acid amide. Especially preferred are the MMP inhibitors currently in clinical development, for example batimastat (2). 20 MMP compounds in clinical development include batimastat (2) for the treatment of malignant pleural effusion, and marimastat (1) for the treatment of pancreatic cancer. Galardin (3) is for the treatment of corneal ulcers, and a specific MMP-1 inhibitor is RO 31-9790 (4).

WO 00/04892 PCTIUS99/13948 -147 Compounds in Clinical Development O 0 H H HOHNOC N HOHNOC N NHMe NHMe OH 0 -0 S (1) (2) O 0 H H HOHNOCN HOHNOC N NHMe - ANHMe 0 -0 NH (3) (4) All that is required to practice the present invention is to administer to a mammal suffering from atherosclerosis, an effective amount of a matrix 5 metalloproteinase inhibitor and an ACAT inhibitor. Compounds which can inhibit the actions of matrix metalloproteinase enzymes can be identified utilizing routine in vitro and in vivo assays. Several compounds from within the foregoing classes have been evaluated in such standard assays and determined to be potent matrix metalloproteinase inhibitors. The assays measure the amount by which a test 10 compound reduces the hydrolysis of a thiopeptolide substrate caused by a matrix metalloproteinase enzyme. Such assays are described in detail by Ye, et al., in Biochemistry, Vol. 31, No 45, 1992, (11231-11235), which is incorporated herein by reference. Thiopeptolide substrates show virtually no decomposition or hydrolysis in 15 the absence of a matrix metalloproteinase enzyme. A typical thiopeptolide substrate commonly utilized for assays is Ac-Pro-Leu-Gly-thioester-Leu-Leu Gly-O Et. A 100 gL assay mixture will contain 50 mM of 2-morpholinoethane sulfonic acid monohydrate (MES, pH 6.0) 10 mM CaCI 2 , 100 gM thiopeptolide WO 00/04892 PCTIUS99/13948 -148 substrate, and 1 mM 5,5'-dithio-bis-(2-nitro-benzoic acid) (DTNB). The thiopeptolide substrate concentration is varied from 10 to 800 gM to obtain Km and Kcat values. The change in absorbance at 405 nm is monitored on a Thermo Max microplate reader (molecular Devices, Menlo Park, CA) at room temperature 5 (22'C). The calculation of the amount of hydrolysis of the thiopeptolide substrate is based on E 4 12 = 13600 m- 1 cm-I for the DTNB-derived product 3-carboxy 4-nitrothiophenoxide. Assays are carried out with and without matrix metalloproteinase inhibitor compounds, and the amount of hydrolysis is compared for a determination of inhibitory activity of the test compounds. 10 Several representative compounds have been evaluated for their ability to inhibit various matrix metalloproteinase enzymes. Table I below presents inhibitory activity for compounds from various classes. In the table, MMP- 1 refers to interstitial collagenase; MMP-2 refers to Gelatinase A; MMP-3 refers to stromelysin; MMP-7 refers to matrilysin; and MMP-9 refers to Gelatinase B. Test 15 compounds were evaluated at various concentrations in order to determine their respective IC 50 values, the micromolar concentration of compound required to cause a 50% inhibition of the hydrolytic activity of the respective enzyme. As noted above, any matrix metalloproteinase inhibitor can be used to treat or prevent atherosclerotic lesions according to this invention. 20 ACAT inhibitors useful in the practice of the instant invention are those of Formula I 0 0 11 ||

R

1

-X-S-N-C-Y-R

2 1 25 || 1 O R or a pharmaceutically acceptable salt thereof wherein: X and Y are selected from oxygen, sulfur and (CR'R")n wherein n is an integer of from 1 to 4 and R' and R' are each independently hydrogen, alkyl, alkoxy, 30 halogen, hydroxy, acyloxy, cycloalkyl, phenyl optionally substituted or R' and R" together form a spirocycloalkyl or a carbonyl; R is hydrogen, a straight or branched alkyl of from I to 8 carbon atoms or benzyl;

R

1 and R 2 are each independently selected from WO 00/04892 PCTIUS99/13948 -149 (a) phenyl or phenoxy each of which is unsubstituted or is substituted with 1 to 5 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and which 5 is straight or branched, an alkoxy group having from I to 6 carbon atoms and which is straight or branched; phenoxy, hydroxy, 10 fluorine, chlorine, bromine, nitro, trifluoromethyl, 15 -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched,

-(CH

2 )pNR 3

R

4 wherein p is zero or one, and each of

R

3 and R 4 is selected from hydrogen or a straight or 20 branched alkyl group having I to 4 carbon atoms; (b) 1- or 2-naphthyl unsubstituted or substituted with from I to 3 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and which 25 is straight or branched, an alkoxy group having from 1 to 6 carbon atoms and which is straight or branched; hydroxy, phenoxy, 30 fluorine, chlorine, WO 00/04892 PCT/US99/13948 -150 bromine, nitro, trifluoromethyl, -COOH, 5 -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched,

-(CH

2 )pNR 3

R

4 wherein p, R 3 and R 4 have the meanings defined above; (c) arylalkyl; 10 (d) a straight or branched alkyl chain having from I to 20 carbon atoms and which is saturated or contains from I to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms. 15 Preferred compounds of the instant invention are those of Formula 1: wherein R 1 is phenyl or is phenyl disubstituted in the 2,6-positions, wherein R 2 is phenyl or is phenyl disubstituted in the 2,6-positions, wherein each of R 1 and R 2 is phenyl, wherein each phenyl is disubstituted in the 2,6-position, 20 wherein R 1 is phenyl disubstituted in the 2,6-positions and R 2 is phenyl trisubstituted in the 2,4,6-positions, wherein R 1 is 2,6-bis(1-methylethyl)phenyl and R2 is 2,6-bis(l methylethyl)phenyl or 2,4,6-tris(I-methylethyl)phenyl, wherein one of R 1 and R 2 is the group 25 R5 -(CH2)t-C-(CH2)w-R 7 , R6 30 wherein t is zero or 1 to 4; w is zero or 1 to 4 with the proviso that the sum of t and w is not greater than 5; WO 00/04892 PCT/US99/13948 -151

R

5 and R 6 are each independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when R 5 is hydrogen, R 6 can be selected from the groups defined for R 7 ; and

R

7 is phenyl or phenyl substituted with from I to 3 substituents selected 5 from a straight or branched alkyl group having from I to 6 carbon atoms, straight or branched alkoxy group having from I to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, COOalkyl wherein alkyl has from 1 to 4 carbon atoms, or -(CH 2 )pNR 3

R

4 wherein P, R 3 and

R

4 have the meanings defined above. 10 Also preferred compounds of the instant invention are those of Formula I wherein X is oxygen, sulfur or (CR'R")n; Y is oxygen, sulfur or (CR'R")n, with the proviso that at least one of X or Y is (CR'R")n wherein n is an integer of from 1 to 4 and R' and R" are each 15 independently hydrogen, straight or branched alkyl of from I to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R" taken together form a carbonyl or a spirocycloalkyl group of from 3 to 10 carbons; R is hydrogen; 20 R 1 is phenyl optionally substituted, straight or branched alkyl of from 1 to 10 carbon atoms, cycloalkyl of from 3 to 10 carbon atoms; R2) is phenyl optionally substituted, straight or branched alkyl of from I to 10 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenoxy optionally substituted with the proviso that only if X is (CR'R")n can 25 R 1 be optionally substituted phenoxy and only if Y is (CR'R")n can R 2 be optionally substituted phenoxy, and with the further proviso that at least one of R 1 and R 2 is optionally substituted phenyl or phenoxy. More preferred compounds of the instant invention are those of Formula I wherein 30 X is oxygen; WO 00/04892 PCT/US99/13948 -152 Y is (CR'R")n wherein n is an integer of from 1 to 2; R is hydrogen;

R

1 is optionally substituted phenyl;

R

2 is optionally substituted phenyl or phenoxy, straight or branched alkyl of from 5 1 to 10 carbons, or cycloalkyl of from 3 to 10 carbons; and R' and R" are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R" taken together form a carbonyl or a spirocycloalkyl. 10 Preferred compounds of Formula I include, but are not limited to the following: Sulfamic acid (phenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid[ [2,4,6-tris(I-methylethyl)phenyl]acetyl-2,6-bis(1-methyl ethyl)phenyl ester, 15 Sulfamic acid[[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6-bis(I-methyl ethyl)phenyl ester, Sulfamic acid [[2,4,6-tris(I-methylethyl)phenyl]acetyl-2,4,6-tris(I-methyl ethyl)phenyl ester, Sulfamic acid[[2,6-bis(1 -methylethyl)phenyl] acetyl]-2,4,6-tris(1-methyl 20 ethyl)phenyl ester, Sulfamic acid[adamantaneacetyl] -2,6-bis [1 -methylethyl)phenyl ester, Sulfamic acid[[2,6-bis(1 -methylethyl)phenyl]acetyl] -2,6-bis(1 -methyl ethyl)phenyl ester-sodium salt, Sulfamic acid[ [2,4,6-tris(1 -methylethyl)phenyl]acetyl] -2,6-bis(1-methyl 25 ethyl)phenyl ester-sodium salt, Sulfamic acid (decanoyl)-2,6-bis-(1-methylethyl)phenyl ester, Sulfamic acid (dodecanoyl)-2,6-bis-(1 -methylethyl)phenyl ester, 2,6-Bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]methyl] sulfonyl]benzeneacetamide, 30 2,6-Bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]methyl] sulfonyl]benzeneacetamide-sodium salt, WO 00/04892 PCT/US99/13948 -153 2,6-Bis(1 -methylethyl)phenyl[[[2,4,6-tris(I -methylethyl)phenyl]methyl] sulfonyl]carbamate, 2,6-Bis(I -methylethyl)phenyl[[[2,4,6-tris(I -methylethyl)phenyl]methyl] sulfonyl]carbamate-sodium salt, 5 Sulfamic acid (1-oxo-3,3-diphenylpropyl)-2,6-bis(I-methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl 10 ester, Sulfamic acid trans-[(2-phenylcyclopropyl)carbonyl] -2,6-bis( 1 methylethyl)phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, 15 Sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, Sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, Sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, 20 Sulfamic acid [3-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(I-methylethyl)phenyl ester, Sulfamic acid (oxophenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [2-trifluoromethylphenyl(acetyl)]-2,6-bis(1 25 methylethyl)phenyl ester, Sulfamic acid (1 -oxo-2-phenylpropyl)-2,6-bis(1 -methylethyl)phenyl ester, Sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(I -methylethyl)phenyl ester, Sulfamic acid (cyclohexylacetyl)-2,6-bis(1 -methylethyl)phenyl ester, 30 Sulfamic acid (diphenylacetyl)-2,6-bis(1 -methylethyl)phenyl ester, Sulfamic acid (triphenylacetyl)-2,6-bis(1 -methylethyl)phenyl ester, Sulfamic acid [(1 -phenylcyclopentyl)carbonyl]-2,6-bis(1 methylethyl)phenyl ester, WO 00/04892 PCT/US99/13948 -154 Sulfamic acid (3-methyl-I -oxo-2-phenylpentyl)-2,6-bis(I methylethyl)phenyl ester, Sulfamic acid (I -oxo-2-phenylbutyl)-2,6-bis(I -methylethyl)phenyl ester, Sulfamic acid (cyclohexylphenylacetyl)-2,6-bis(1 -methylethyl)phenyl 5 ester, Sulfamic acid (1-oxo-2,2-diphenylpropyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [(9H-fluoren-9-yl)carbonyl]-2,6-bis(1-methylethyl)phenyl ester, 10 Sulfamic acid (1-oxo-3-phenylpropyl)-2,6-bis(I-methylethyl)phenyl ester, Sulfamic acid [1-oxo-3-[2,4,6-tris(1-methylethyl)phenyl]-2-propenyl] 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [1 -oxo-3 -[2,4,6-tris(I -methylethyl)phenyl]propyl] 2,6-bis(1-methylethyl)phenyl ester, 15 Sulfamic acid [(acetyloxy)[2,4,6-tris(1-methylethyl)phenyl]acetyl] 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [hydroxy[2,4,6-tris(1-methylethyl)phenyl]acetyl] 2,6-bis(I -methylethyl)phenyl ester, Sulfamic acid [fluoro[2,4,6-tris(1-methylethyl)phenyl]acetyl] 20 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid (3-methyl-i -oxo-2-phenylpentyl)-2,6-bis(1 methylethyl)phenyl ester sodium salt, Sulfamic acid [[2,4,6-tris(1-methylethyl)phenoxy]acetyl]-2,6-bis(1 methylethyl)phenyl ester, 25 Sulfamic acid [[2,6-bis(I-methylethyl)phenoxy]acetyl]-2,6-bis(1 methylethyl)phenyl ester, and Sulfamic acid [[2,4,6-tris(I-methylethyl)phenyl]acetyl] 2,6-bis(phenyl)phenyl ester. Other ACAT inhibitors useful in the practice of this invention are selected 30 from: 4-Hexadecylamino-benzoic acid monosodium salt; 3,5-Dimethyl- I -[5-(1, 4 ,5-triphenyl-2H-imidazol-2-ylsulfanyl)-pentyl]- 1 H pyrazole monosodium salt; WO 00/04892 PCT/US99/13948 -155 8-(1, 4 ,5-Triphenyl-2H-imidazol-2-yloxy)-octanoic acid; 9-Bromo-6, 11 -dihydro-dibenzo[b,e]oxepine- 11 -carboxylic acid (2,6 diisopropyl-phenyl)-amide; 5-((3,5-Di-tert-butyl-4-hydroxy-phenylamino)-

{[

4

-(

2 ,2-dimethyl-propyl) 5 benzyl]-hexyl-amino } -methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione; 3-(2,4-Difluoro-phenyl)- I -[ 4

-(

2 ,2-dimethyl-propyl)-benzyl] -1 -heptyl-urea; 1 -Heptyl- 1-[4-(3-methyl-butyl)-benzyl]-3-( 2

,

4

,

6 -trifluoro-phenyl)-urea; 3-(2,4-Difluoro-phenyl)- 1-[5-(4,5-diphenyl- 1 H-imidazol-2-ylsulfanyl) pentyl]- 1 -heptyl-urea; 10 1 -Butyl-3- { 2-[3-(5-ethyl-4-phenyl-imidazol- I -yl)-propoxy]-6-methyl phenyl } -urea; 1-(2- {2- [ 4 -(2,2-Dimethyl-propyl)-phenyl] -ethyl } -4,6-difluoro-phenyl) 3-heptyl-urea; Octadeca-9,12-dienoic acid (1 -phenyl-ethyl)-amide; 15 3-(1H-Indol-3-yl)- 2 -octadec-9-enoylamino-propionic acid ethyl ester; 3-(Dimethyl-nonyl-silanyl)-N-(1 -phenyl- 2 -p-tolyl-ethyl)-propionamide; (R)2-Hexyl-decanoic acid ( 6 -methyl-2,4-bis-methylsulfanyl-pyridin-3-yl) amide; N-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-ethyl]-4-fluoro 20 benzenesulfonamide; 2 -(2-Ethoxy-ethylsulfanyl)-4,5-diphenyl-1 H-imidazole; 4-Cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyl 4,5-dihydro-3H-imidazol-4-yl]-N-methyl-benzamide; 1- { 3-[3-(1-Methyl-1H-imidazol-2-yl)-2-phenethyl-2H-chromen-6-yloxy] 25 propyl}-cyclopentanecarboxylic acid ethyl ester; 1-[ 4 -(2-Chloro-phenyl)-2-ethyl-thieno[2,3-b]pyridin-5-yl] -3-(2,4-difluoro phenyl)-urea; 1-(2-Cyclohexyl-[ 1,3]dithiolan-2-ylmethyl)-3-(2,6-diisopropyl-phenyl) urea; 30 1 -Cycloheptyl- 1 -(2,3-dihydro-benzo[ 1,4]dioxin-5-ylmethyl) 3-( 2

,

4 ,6-trimethyl-phenyl)-urea; 1- {2-[4-(1, 2 -Dimethoxy-ethoxy)-phenyl] -ethyl } -3-(2,4-dimethoxy phenyl)- I -heptyl-urea; WO 00/04892 PCT/US99/13948 -156 2-(4- {2-[3-(2,4-Dimethoxy-phenyl)- I -heptyl-ureido] -ethyl } -phenoxy) 2-methyl-propionic acid; 3-(2,4-Difluoro-phenyl)-1-octyl-1-(2,3,4,5-tetrahydro-benzo[b]oxepin 5-yl)-urea; 5 N-( 2

,

6 -Diisopropyl-phenyl)-2-octadecylsulfanyl-acetamide; 2-Bromo-6,11-dihydro-dibenzo[b,e]oxepine- 11 -carboxylic acid (2,6-diisopropyl-phenyl)-amide; (±)N-(1,2-Diphenyl-ethyl)-3-( 2 -heptyloxy-phenyl)-propionamide; 2,2-Dimethyl-dodecanoic acid ( 7 -methoxy-4-oxo-chroman-8-yl)-amide; 10 (Z) I -(6,7-Dimethoxy-3,4-dihydro- 1 H-isoquinolin-2-yl)-octadec-9-en 1-one; (Z)2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid [2-(2-octadec 9-enoylamino-ethylcarbamoyl)-ethyl]-amide; I-Benzyl-1-(5-methyl-3-phenyl-benzofuran-2-ylmethyl)-3-(2,4,6-trifluoro 15 phenyl)-urea; 5-Chloro-3-o-tolyl-benzofuran-2-carboxylic acid (2,6-diisopropyl-phenyl) amide; 2-(2,4a-Dimethyl-4a,5-dihydro-naphthalen-1-ylsulfanyl)-N-{2-[(6,6 dimethyl-hepta-2,4-diynyl)-pentyl-amino]-ethyl } -acetamide; 20 (Z)Octadec-9-enoic acid [2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-1-phenyl ethyl]-amide;

N-(

4 -Dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl)-4-(phenyl propyl-amino)-butyramide; (Z)1 -(6,7-Dimethoxy-3-phenyl-3,4-dihydro- 1 H-isoquinolin-2-yl)-octadec 25 9-en-I-one; (trans) 1, 4 -Bis-( 4 -methoxy-phenyl)-3-(3-phenyl-propyl)-azetidin-2-one; 1 -Butyl-3- { 2-dimethylamino-6-[3-(4-phenyl-imidazol- I -yl)-propoxy] phenyl } -urea; 1- { 2-Dimethylamino-6- [3 -(4-phenyl-imidazol- I -yl)-propoxy] -phenyl} 30 3-pentyl-urea; 1- { 2-Dimethylamino-6-[3 -(5-methyl-4-phenyl-imidazol- I -yl)-propoxy] phenyl} -3-pentyl-urea; WO 00/04892 PCT/US99/13948 -157 1-(2- {2-[4-(2,2-Dimethyl-propyl)-phenyl] -ethyl } -4,6-difluoro-phenyl) 3-heptyl-urea; (4S-trans)6-(4,5-Diphenyl- 1 H-imidazol-2-ylsulfanylmethyl)-4-hydroxy 4 -methyl-tetrahydro-pyran-2-one; 5 2-(3-[1, 3 ]Dioxan-2-yl-propylsulfanyl)-4,5-diphenyl- 1 H-imidazole; Hydroxy-phenyl-acetic acid 3,3,5-trimethyl-cyclohexyl ester; Acetic acid 1 -(11 -hydroxy-4-methoxy-9-methyl-5-oxo-5H,7H-6,12-dioxa dibenzo[a,d]cycloocten-3-yl)-3-methyl-butyl ester; I 0-Hydroxy-2,4a,6a,6b,9,10,1 2 a-heptamethyl-4-octadecanoyloxy 10 1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10, 11,12,12a,12b,13,14b-eicosahydro-picene 2-carboxylic acid; 3-[(2,2,5,5-Tetramethyl-[1,3]dioxane-4-carbonyl)-amino]-propionic acid 2-[3-(2,2-dimethyl-propyl)-3-nonyl-ureido]-cyclohexyl ester; 1-(2,6-Diisopropyl-phenyl)-3-( 2 -p-tolyl-heptyl)-urea; 15 1-[4-(2-Chloro-phenyl)-6,8-dimethyl-quinolin-3-yl]-3-(2,4-difluoro phenyl)-urea; 1-[4-(2-Chloro-phenyl)-1,6,7-trimethyl-2-oxo-1,2-dihydro-quinolin-3-yl] 3-(2,4-difluoro-phenyl)-urea; 1-[ 4

-(

2 -Chloro-phenyl)-6,7-dimethyl-2-oxo-2H-chromen-3-yl] 20 3-(2,4-difluoro-phenyl)-urea; (S)1-[6-Bromo-5-(2-chloro-phenyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H benzo[e][1,4]diazepin-7-yl]-3-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-urea; 3-(4,5-Diphenyl- 1 H-imidazol-2-ylsulfanylmethyl)- 1 -methyl-piperidine; 2-(5,5-Dimethyl-[ 1,3]dioxan-2-yl)-4,5-diphenyl- 1 H-imidazole; 25 2,2-Dimethyl-5-[3-(1-methyl- IH-imidazol-2-yl)-2-propyl-chroman 6 -yloxy]-pentanoic acid ethyl ester;

N-(

4 -Hexadecylamino-benzoyl)-4-methyl-benzenesulfonamide; 2-(4-Chloro-phenyl)-6-cyclohexyl-4-(2-oxo-2-phenyl-ethyl)-6,7-dihydro 4H- 1, 4 ,6,8a-tetraaza-s-indacene-5,8-dione; 30 [2-(3 -tert-Butyl-4-hydroxy-naphthalen- 1 -yl)- 1 -(diethoxy-phosphoryl) vinyl] -phosphonic acid diethyl ester; WO 00/04892 PCT/US99/13948 -158 5- [1 -(acetyloxy)-3-methylbutyl]-2'-(hydroxymethyl)-4-methoxy-4' methylspiro[benzofuran-2(3H), I'-cyclohexa-2',4'-diene]-3,6'-dione; 5-[ 1 -(acetyloxy)-3-methylbutyl]-4-methoxy-4'-methyl 3,6-dioxospiro[benzofuran-2(3H), 1'-cyclohexa-2',4'-diene]-2'-carboxaldehyde; 5 (3a,4ct,22a,24a)-3-hydroxy-22-[(1 -oxooctadecyl)oxy]-24-norolean- 12-en 29-oic acid; 1-[5-(4,5-Diphenyl-1H-imidazole-2-sulfinyl)-pentyl]-3,5-dimethyl-IH pyrazole; and N-butyl-3 -[[(4-decyloxyphenyl)carbonyl] amino] -4-(methylthio) 10 benzamide;

CH

3 O

H

3 N N N o H H Bay 02752 H H NyN N N ; and

(H

3

C)

2 N

N(CH

3

)

2 YM-17E N N ' S N H RP73163 The compounds, both ACAT and MMP inhibitors, include all possible 15 stereoisomers.

WO 00/04892 PCT/US99/13948 -159 METHODS The direct antiatherosclerotic potential of ACAT and MMP inhibitors is evaluated in a model of atherosclerotic lesion regression. Male New Zealand White rabbits (Kuiper Farms, Gary, Indiana) weighing 1.2 to 1.5 kg are meal-fed a 5 chow diet (Purina 5321) supplemented with 0.5% cholesterol (C), 3% peanut (PNO) oil, and 3% coconut (CNO) oil diet for a total of 9 weeks followed by a 0% C, 3% PNO, and 3% CNO diet (chow/fat diet) for 6 weeks prior to an 8-week administration of the ACAT inhibitor; for example, sulfamic acid[[2,4,6-tris (1-methylethyl)phenyl]acetyl-2,6-bis(I-methylethyl)phenyl ester, the HMG-CoA 10 reductase inhibitor, for example, simvastatin, either alone or together. The dietary regimen consists of feeding 30 g for the first week, 40 g for 2 weeks, 50 g for 2 weeks, 60 g for 4 weeks, 70 g for the next 6 weeks, and 80 g for the final 8 weeks. After I week of diet initiation, a chronic endothelial injury is induced in the abdominal aorta and femoral artery by surgically inserting a sterile, 15 indwelling, 18-cm nylon monofilament with a diameter of 200 pM into the lumen of the right femoral artery. After the initial 15-week lesion induction phase, which consists of both a hypercholesterolemic and plasma cholesterol normalization stage, the animals are randomized on the basis of their 24-hour postmeal plasma total cholesterol values into groups which are not statistically different. A group of 20 animals, termed the time zero control (n = 16), is necropsied prior to drug administration while a second group, termed the progression control (n = 16), is maintained on the chow/fat diet for the remaining 8 weeks of the study. Additional groups of animals are administered either ACAT inhibitors, MMP inhibitors, or coadministered both compounds. 25 Other ACAT inhibitors useful in the practice of the instant invention are those of Formula 1 below 0 N R -- N-C-(CH 2 )ij-C 4 1 H / \ N

R

2 R 3 wherein n is zero, one or two; wherein R 1 is selected from WO 00/04892 PCT/US99/13948 -160 (a) phenyl which is unsubstituted or is substituted with from one to three substituents selected from: alkyl having from 1 to 4 carbon atoms and which is straight or branched, alkoxy having from 1 to 3 carbon atoms and which is straight or branched, 5 alkylthio having from 1 to 3 carbon atoms and which is straight or branched, hydroxy, phenyl, fluorine, 10 chlorine, bromine, nitro, cyano, trifluoromethyl, 15 -COOH, -COOalkyl wherein alkyl has from I to 4 carbon atoms and which is straight or branched, -(CH2)mNR5R 6 wherein m is zero or one, and each of R 5 and R 6 is hydrogen or a straight or branched alkyl group having 1 to 4 carbon 20 atoms; (b) I - or 2-naphthyl which is unsubstituted or substituted with I to 3 substituents selected from: alkyl having from 1 to 4 carbon atoms and which is straight or branched, alkoxy having from 1 to 3 carbon atoms and which is straight or branched, 25 hydroxy, fluorine, chlorine, bromine, nitro, 30 cyano, trifluoromethyl,

-COOH,

WO 00/04892 PCT/US99/13948 -161 -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, -(CH2)mNR5R 6 wherein m, R 5 , and R 6 have the meanings defined above; (c) the group

OR

7 N (O

N*

5

-OR

7 wherein R 7 is a lower alkyl group having from 1 to 3 carbon atoms and is straight or branched; (d) the group 8

N

N

R

1 0 R 9 10 wherein R 8 and R 9 are straight or branched alkyl having from I to 4 carbon atoms or phenyl, and R 10 is a straight or branched hydrocarbon group having from I to 18 carbon atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds; phenyl; phenyl substituted with from 15 one to three substituents selected from straight or branched alkyl having I to 4 carbon atoms, straight or branched alkoxy having from 1 to 3 carbon atoms, hydroxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from I to 4 carbon atoms and is straight or branched or 20 -(CH2)mNR5R 6 wherein m, R 5 , and R 6 are as defined above; or a heterocyclic group selected from 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, or 3- or 4-pyridazinyl and the N-oxides thereof; (e) the group WO 00/04892 PCT/US99/13948 -162

CH

3 00 0;

CH

3 N N (f) the group 0

H

3 Cl 00

CH

3 N (g) a straight or branched hydrocarbon group having from I to 18 carbon 5 atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds; (h) a cycloalkyl group having from 3 to 8 carbon atoms; (i) a heteroaromatic group selected from 2-, 3-, or 4-pyridyl which is unsubstituted or substituted with an alkyl group having from I to 4 carbon 10 atoms or 2-, 4-, or 5-pyrimidinyl, and the N-oxides thereof; (j) the group Ri n' Y 0 0 Z wherein --- denotes a single or double bond; Y and Z are each independently hydrogen, a straight or branched alkyl group of I to 15 4 carbon atoms, an alkoxy group of I to 3 carbon atoms or halo; X is oxygen or two hydrogen atoms;

R

1 I is hydrogen or a straight or branched alkyl group of I to 4 carbon atoms, and n' is zero or one; or WO 00/04892 PCT/US99/13948 -163 (k) is selected from the group B E / 13 R12 R13 R12 R14 R15R1 R13and R14 3 N 12 wherein R 12, R 13, R 14, and R 15 are each independently hydrogen, halo, a straight or branched alkyl group of I to 4 carbon atoms, an alkoxy 5 group of I to 3 carbon atoms, and alkylthio group of I to 3 carbon atoms, cycloaklylthio of five to seven carbon atoms, phenylalkylthio in which alkyl is I to 4 carbon atoms, substituted phenylthio, heteroarylthio, or heteroaryloxy; and B, D, E, and G are nitrogen or carbon where one or more of B, D, and E is 10 nitrogen; with the proviso that when G = nitrogen the group is attached to the nitrogen atom of Formula I at the 4- or 5-position of the pyrimidine ring (a and b); wherein R2 and R3 are the same or different and are selected from: (a) hydrogen, halo or one of R2 or R3 is hydroxy; 15 (b) a straight or branched alkyl group having from I to 12 carbon atoms, or a cycloalkyl group having from 3 to 8 carbon atoms; (c) a phenyl or phenylalkyl group where alkyl is from I to 4 carbon atoms and which the phenyl ring unsubstituted or substituted with from 1 to 3 substituents selected from straight or branched alkyl having from I to 20 4 carbon atoms, straight or branched alkoxy having from I to 4 carbon atoms, alkythio, straight or branched having I to 4 carbon atoms, hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro, phenyl, or (CH2)mNR5R6 wherein m, R5, and R6 have the meanings defined above; (d) a straight or branched alkenyl group having from 2 to 6 carbon atoms; or WO 00/04892 PCT/US99/13948 -164 (e) R 2 and R 3 taken together with the carbon atom to which they are attached form an alkylidene group of 1 to 4 carbon atoms, a benzylidene or a spiroalkyl group having from 3 to 7 carbon atoms; or (f) when R 2 is hydrogen, F, alkyl of C 1- 12 atoms, R 3 is a heteroaryl selected 5 from a 5- or 6-membered monocyclic or fused bicyclic heterocyclic group containing at least I to 4 heteroatoms in at least one ring, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heterocyclic group being unsubstituted or substituted with an alkyl group having from I to 4 carbon atoms and the N-oxides thereof; 10 (g) 1- or 2-naphthyl which is unsubstituted or substituted with I to 3 substituents selected from: alkyl having from I to 4 carbon atoms and which is straight or branched, alkoxy having from 1 to 3 carbon atoms and which is straight or branched, wherein R 4 is a straight or branched hydrocarbon chain having from 1 to 15 20 carbon atoms and is saturated or is unsaturated and has 1 double bond or has 2 nonadjacent double bonds or is alkylthio having 1 to 20 carbon atoms and is saturated; or a pharmaceutically acceptable salt or individual enantiomeric isomer thereof. Specifically,the following compounds are useful in the instant invention: 20 N-[2,6-Bis(I -methylethyl)phenyl]-2-dodecyl-2H-tetrazole-5-acetamide; 2 -Dodecyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide; N-(2,4-Difluorophenyl)-2-dodecyl-2H-tetrazole-5-acetamide; 2 -Tetradecyl-N-(2,4,6-tri-methoxyphenyl)-2H-tetrazole-5-acetamide;

N-(

4 ,6-Dimethoxy-5-pyrimidinyl)-2-dodecyl-2H-tetrazole-5-acetamide; 25 N-(4,6-Dimethoxy-5-pyrimidinyl)-2-dodecyl- 1 H-tetrazole-5-acetamide; 2-Dodecyl-N-(3-methyl-2-pyridinyl)-2H-tetrazole-5-acetamide; 2-Dodecyl-N-(1,3,5-trimethyl- 1 H-pyrazol-4-yl)-2H-tetrazole-5-acetamide; 1 -Dodecyl-N-(1,3,5-trimethyl- I H-pyrazol-4-yl)- I H-tetrazole-5-acetamide; (±) 2-Dodecyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole 30 5-acetamide; (±) 2-Dodecyl-N,c-diphenyl-2H-tetrazole-5-acetamide; WO 00/04892 PCTIUS99/13948 -165 (±)-N-[2,6-bis( 1 -Methylethyl)phenyl]-2-dodecy1-(x-pheny12H-tetrazole 5-acetamide;

(±)-N-(

2 ,4-Difluorophenyl)-2-dodecyl-cx-phenyl-2H-tetrazole. 5-acetamide; 5 (±)- 2 -Octyl-ux-phenyl-N-(2,4,6-trimethoxyphenyl)>2H-tetrazole 5-acetamide;

(±)-

2 -Hexadecyl-cc-pheny1-N-(2,4,6-trimethoxyphenyl)>2Htetrazole 5-acetamide; (±--46Dmtoy5prmdnl--oey-xpey-Httaoe 10 5-acetamide; (±)-N-(5,7-Dimethyl- I ,8-naphthyridine-2-yl)-2-dodecylc-phenyl.2H. tetrazole-5-acetamide; (±)-2-Dodecyl-(x-phenyl-N-( 1,3 ,5-trimethyl- 1 H-pyrazol-4-yl)-2H tetrazole-5 -acetamide; 15 (±)-N-Cyclopropyl-2-dodecyl-cx-pheny1-2Htetrazole-5.acetamide;

(±)-

2 -Dodecyl-c(-phenyl-N-2-pyridinyl-2H-tetrazole-5acetamide; (±)-2-Dodecyl-N-(3 -methyl- 2 -pyridiny1)-u-phenyl-2H-tetrazole 5-acetamide; (±)-2-Dodecyl-N-(3 -methyl- 2 -pyridinyl)-2-phenyl-2H-tetrazole 20 5-acetamide, N-oxide; (±)-N-(, 1, -Dimethylethyl)-2-dodecy1-ca-pheny2Htetrazole5acetamide;

(±)-

2 -Dodecyl-ct-( 2 -pyridyl)-N-(2,4,6-trimethoxyphenyl)>2H-tetrazole. 5-acetamide; (±)-N- [2,6-Bis( 1 -methylethyl)phenyl] -2-dodecyl-cx-2-pyridinyl-2H 25 tetrazole-5-acetamide; 2 -Dodecyl-a,a-dimethyl-N-(2,4,6-trimethoxyphenyl)>2Htetrazole. 5 -acetamide; 2 -Dodecyl-cx,Wx-( 2 -propenyl)-N-(2,4,6-trimethoxyphenyl)y2Htetrazole 5-acetamide; 30 1 -( 2 -Dodecy1-2H-tetrazo1-5-y)-N-(2,4,6-trimethoxypheny1> yclopentanecarboxamide; WO 00/04892 PCT/US99/13948 -166 2 -Tridecyl-c~a-dimethyl-N-(2,4,6-trimethoxyphenyl)>2H-tetrazole 5-acetamide; 2 -Dodecyl-N-(2,4,6-trimethoxypheny)-2H-tetrazoe5propanamide; N-(2,6-bis( I -Methylethyl)phenyl)-2-dodecyl-2H-tetrazole..Spropanamide; 5 N-( 2

,

4 -Difluorophenyl)-2-dodecyl-2H-tetrazole-5-propanamide; I -Dodecyl-N-(2,4,6-trimethoxyphenyl)- 1 H-tetrazole-5-propanamide; (±)-n-(2,4-Difluorophenyl)- I -dodecyl-ix-phenyl- 1 H-tetrazole-5-acetamide; (±)-N-[2,6-bis( 1 -Methylethyl)phenyl] -1I -dodecyl-aX-phenyl- 1 H-tetrazole 5-acetamnide; 10 (±)-2-Dodecy1-cc-methyl-c-pheny-N-(2,4,6-trimethoxyphenyl)>2H tetrazole-5-acetamide;

(±)-

2 -Dodecyl-ou-(4-fluorophenyl)-N-(2,4,6-trimethoxyphenyl)2H tetrazole-5-acetamide; (±)-2-Dodecy1-cc-2-naphthalenyl-N-(2,4,6-trimethoxyphenyl)-2H. 15 tetrazole-5-acetamide; (±)-c-([ 1,1 '-Biphenyl] - 4 -yl)- 2 -dodecy1-N-(2,4,6-trimethoxy-phenyl)>2H tetrazole-5-acetamide;

(±)-

2 -Dodecyl-u-methyl-N-(2,4,6-trimethoxy-phenyl)>2Htetrazole. 5-acetamide; 20 (±)- 2 -Dodecyl--phenylmethy1-N-(2,4,6-trimethoxyphenyl)>2H-tetrazole 5-acetamide;

(±)-

2 -Dodecyl-cx-cyclohexyl-N-(2,4,6-trimethoxy-phenyl)>2H-tetrazole 5-acetamide;

(-)-

2 -Dodecyl-cwphenyl-N-(2,4,6-trimethoxy-phenyl)-2H-tetrazole 25 5-acetamide [a]ID = -58' (1% in CH 3 OH);

(+)-

2 -Dodecyl-ux-phenyl-N-(2,4,6-trimethoxy-phenyl)2H-tetrazole. 5-acetamide [a]ID = +55.10 (1% in CH 3 OH); (±)-N- [2,6-Bis( I -Methylethyl)phenyl] -2-dodecyl-ax-fluoro-o-phenyl-2Hl tetrazole-5 -acetamide; 30 (±)- 2 -Dodecyl-u.fluoro-cc-phenyl-N-(2,4,6-trimethoxy phenyl)-2H tetrazole-5 -acetamide; WO 00/04892 PCT/US99/13948 -167 N-[2,6-bis(I -Methylethyl)phenyl]-5-decyl-2H-tetrazole-2-acetamide; N-[2,6-bis(I -Methylethyl)phenyl-5-dodecyl-2H-tetrazole-2-acetamide; (±)-N-[2,6-bis(I -Methylethyl)phenyl]-5-dodecyl-ax-phenyl-2H-tetrazole 2-acetamide; 5 (±)-N-[2,6-bis(I -Methylethyl)phenyl]-5-dodecyl-a-pentyl-2H-tetrazole 2-acetamide; (±)-N-[2,6-bis(1 -Methylethyl)phenyl-5-(dodecylthio)-X-phenyl-2H tetrazole-2-acetamide; (±)-5-Decyl-a-phenyl-N-(2,4,6-trimethoxyphenyl-2H-tetrazole 10 2-acetamide; 5-Dodecyl-N-( 2

,

4

,

6 -trimethoxy-phenyl)-2H-tetrazole-2-acetamide; (±)-5-Dodecyl-a-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole 2-acetamide; (±)-5-Dodecyl-u-pentyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole 15 2-acetamide;

(±)-N-(

2

,

4 -Difluorophenyl-5-dodecyl-c-phenyl-2H-tetrazole-2-acetamide; 5-Dodecyl-x,ax-dimethyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole 2-acetamide; (±)-5-(Dodecylthio)-ax-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole 20 2-acetamide; or (±)-5-(Dodecylsulfinyl)-a-phenyl-N-(2,4,6)-trimethoxyphenyl)-2H tetrazole-2-acetamide. The compounds to be employed in the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms for treating 25 and preventing atherosclerosis. The compounds can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds can be administered by inhalation, for example, intranasally. Additionally, the compounds can be administered transdermally. It will be obvious to those skilled in the art that the 30 following dosage forms may comprise as the active component, either a compound as a free base, acid, or a corresponding pharmaceutically acceptable WO 00/04892 PCT/US99/13948 -168 salt of such compound. The active compound generally is present in a concentration of about 5% to about 95% by weight of the formulation. For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or 5 liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. 10 In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. 15 The powders and tablets preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation 20 of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. 25 For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. 30 Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

WO 00/04892 PCTIUS99/13948 -169 Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the 5 finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. 10 Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The pharmaceutical preparation is preferably in unit dosage form. In such 15 form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the 20 appropriate number of any of these in packaged form. The quantity of active component in a unit-dose preparation may be varied or adjusted from I to 1000 mg, preferably 10 to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. 25 The compounds utilized in the pharmaceutical method of this invention are administered at a dose that is effective to inhibit the hydrolytic activity of one or more matrix metalloproteinase enzymes. Such effective amounts are thus those which prevent or treat CHF and ventricular dilatation. The compounds can also be used prophalactically at the same dose levels. The initial dosage of about 1 mg to 30 about 100 mg per kilogram daily will be effective to prevent and treat heart failure. A daily dose range of about 5 to about 75 mg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.

WO 00/04892 PCT/US99/13948 -170 Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For 5 convenience, the total daily dosage may be divided and administered in portions during the day if desired. Typical dosages will be from about 0.1 to about 500 mg/kg, and ideally about 25 to about 250 mg/kg. The following examples illustrate typical formulations that can be utilized in the invention. 10 Tablet Formulation Ingredient Amount (mg) 2 -(4'-bromobiphenyl-4-sulfonylamino)-3-methyl- 25 butyric acid ACAT Compound Lactose 50 Corn starch (for mix) 10 Corn starch (paste) 10 Magnesium stearate (1%) 5 Total 100 The biphenylsulfonamide, lactose, and corn starch (for mix) are blended to uniformity. The corn starch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed 15 powders. The wet granules are passed through a No. 8 hand screen and dried at 80'C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. Such tablets can be administered to a human from one to four times a day for treatment of atherosclerosis and arthritis.

WO 00/04892 PCT/US99/13948 -171 Preparation for Oral Solution Ingredient Amount (R)-2-(4'-Cyanobiphenyl-4-sulfonylamino)-3-phenyl- 400 mg propionic acid sodium salt ACAT Compound Sorbitol solution (70% N.F.) 40 mL Sodium benzoate 20 mg Saccharin 5 mg Red dye 10 mg Cherry flavor 20 mg Distilled water q.s. 100 mL The sorbitol solution is added to 40 mL of distilled water, and the biphenylsulfonamide is dissolved therein. The saccharin, sodium benzoate, flavor, 5 and dye are added and dissolved. The volume is adjusted to 100 mL with distilled water. Each milliliter of syrup contains 4 mg of invention compound. Parenteral Solution In a solution of 700 mL of propylene glycol and 200 mL of water for injection is suspended 20 g of (S)- 2

-(

4 '-amino-biphenyl-4-sulfonylamino) 10 3-(3-ethoxyphenyl)-propionic acid. After suspension is complete, the pH is adjusted to 6.5 with IN sodium hydroxide, and the volume is made up to 1000 mL with water for injection. The formulation is sterilized, filled into 5.0 mL ampoules each containing 2.0 mL, and sealed under nitrogen.

Claims (36)

1. A method for treating and/or preventing atherosclerotic lesions in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of an ACAT inhibitor with a 5 therapeutically effective amount of a MMP inhibitor.

2. A method for preventing plaque rupture and for promoting lesion regression in a mammal in need of said treatment and/or prevention comprising administering to said mammal a therapeutically effective amount of an ACAT inhibitor with a therapeutically effective amount of a 10 MMP inhibitor.

3. A method according to Claim 1 utilizing a compound of the formula R R2 Rl wherein: A is a bond, CONH, or -Y N- , where Y is CH or N; 15 RI is alkyl, aryl, halo, amino, substituted or disubstituted amino, or alkoxy; R 2 is carboxyalkyl ketone or oxime, carboxyalkylsulfonamide, or -S0 2 -NHCHCOOH; and 20 R3 R 3 is alkyl, substituted alkyl, amino, substituted or disubstituted amino, or aryl, and pharmaceutically acceptable salts thereof.

4. A method of Claim 3 utilizing a compound of the formula / Y N R WO 00/04892 PCTIUS99/13948 -173

5. A method according to Claim 3 employing a compound of the formula Ri R2

6. A method according to Claim 4 employing a compound of the formula 0 R-N-C-COR 3 RI~ ~ / H ~ OR2 5 wherein: R 1 is C 1 -C 6 alkyl, halo, nitro, NR 4 R 5 , cyano, OR 4 , and COOR 4 ; R 2 is CI-C 6 alkyl, optionally substituted by phenyl, substituted phenyl, NH 10 NR 4 R 5 , OR 6 , carboxy, carboxamido, H 2 N-C-NH-, thio, methylthio, indole, imidazole, phthalimido, phenyl, and substituted phenyl; R 3 is OH, OCI -C 6 alkyl, or NHOH; R 4 is hydrogen, C 1 -C 6 alkyl, or CI-C 6 alkanoyl; 15 R 5 is hydrogen or CI-C 6 alkyl; and R 6 is hydrogen, CI-C 6 alkyl, CI-C 6 alkanoyl, phenyl, or substituted phenyl.

7. A method according to Claim 5 employing a compound of the formula 0 0 -RI- - -iO R1/\ -O S-N-C-COH U R2 20

8. A method according to Claim 6 employing 2-(4'-bromobiphenyl 4-sulfonylamino)-3-methyl-butyric acid. WO 00/04892 PCT/US99/13948 -174

9. A method according to Claim 2 employing a compound of the formula /R 3 R 4 0 R 0 --- C--C---R5 R -3 I 4 Rl wherein R and R I are the same or different and are hydrogen, 5 alkyl, halogen, nitro, yano, rifluoromethyl, 10 OR 6 wherein R 6 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or 15 cycloalkyl, -N-R 6 wherein R 6 and R 6 a are the same or different and are R6a as defined above for R 6 , 20 0 II -O-C-R 6 wherein R 6 is as defined above, 0 || 25 -NH-C-R 6 wherein R 6 is as defined above, 0 II -S-C-R 6 wherein R 6 is as defined above, -SR 6 wherein R 6 is as defined above, WO 00/04892 PCT/US99/13948 -175 0 || -C-R 6 wherein R 6 is as defined above, -CH 2 -OR 6 wherein R 6 is as defined above, 5 -CH 2 -N-R 6 wherein R 6 and R 6 a are the same or different R6a and are as defined above for R 6 , 0 10 || -C-N-R 6 wherein R 6 and R 6 a are the same or different and R6a are as defined above for R 6 , 15 0 -S-R 6 wherein R 6 is as defined above, || 20 cycloalkyl, or heteroaryl, with the proviso that R and RI are not both hydrogen; R 2 is -OR 6 wherein R 6 is as defined above, or -N-R 6 wherein R 6 and R 6 a are the same or different and are 25 R6a as defined above for R 6 ; R 3 , R 3 a, R 4 , and R 4 a are the same or different and are hydrogen, fluorine, alkyl, 30 -(CH2)n-aryl wherein n is an integer from 1 to 6, -(CH 2 )n-heteroaryl wherein n is as defined above, -(CH2)n-cycloalkyl wherein n is as defined above, WO 00/04892 PCT/US99/13948 -176 -(CH2)p-X-(CH 2 )q-aryl wherein X is 0, S, SO, SO 2 , or NH, and p and q are each zero or an integer of I to 6, and the sum of p + q is not greater than six, -(CH2)p-X-(CH 2 )q-heteroaryl wherein X, p, and q are as defined 5 above, or -(CH2)n-R 7 wherein R 7 is N-phthalimido, N-2,3-naphthyimido, -OR 6 wherein R 6 is as defined above, 10 -N-R 6 wherein R 6 and R 6 a are the same or different and R6a are as defined above for R 6 , -SR 6 where R 6 is as defined above, 15 0 II -S-R 6 wherein R 6 is as defined above, 0 20 -S-R 6 wherein R 6 is as defined above, 11 0 25 -O-C-R 6 wherein R 6 is as defined above, 0 -N-C-R 6 wherein R 6 and R 6 a are the same or different 30 R6a and are as defined above for R 6 , 0 -S-C-R 6 wherein R 6 is as defined above, WO 00/04892 PCT/US99/13948 -177 0 II -C-R 6 wherein R 6 is as defined above, 0 5 || -C-OR 6 wherein R 6 is as defined above, or 0 -C-N-R 6 wherein R 6 and R 6 a are the same or different 10 R6a and are as defined above for R 6 , and n is as defined above; R 5 is OH or SH; with the proviso that R 3 , R 3 a, R 4 , and 15 R 4 a are hydrogen or at least one of R 3 , R 3 a, R 4 , or R 4 a is fluorine; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.

10. A method according to Claim 8 employing a compound of the formula N OH 0 R C/ \ /C-CH 2 CH 2 C-OH 20

11. A method according to Claim 9 employing 4-(4'-chlorobiphenyl-4-yl) 4-hydroxyimino-butyric acid.

12. A method according to Claim 1 employing a compound of the formula X R2 25 wherein X is oxygen or -C-CH 2 - WO 00/04892 PCT/US99/13948 -178 NOH R 2 is -C-CH 2 CH-COOH or -SO 2 NHCHCOOH; and 5 R3 R3 R 3 is alkyl, halo, alkoxy, acyl, or aryl.

13. A method according to Claim 11 employing a compound of the formula X 0 2 NHCH-COOH R3

14. A method according to Claim 12 employing (S)-2-(9H-fluorene 10 2-sulfonylamino)-4-phenyl-butyric acid.

15. A method according to Claim 12 employing O SO 2 NH CO 2 H

16. A method according to Claim I employing a compound of formula I 0 1- - COR3 R O R2 15 wherein: R I is C 1 -C 6 alkyl, halo, nitro, (CH 2 ) 0 - 4 -NR 4 R 5 , 0 0 cyano, OR 4 , CH, CF 3 , CNR 4 R 5 , and COOR 4 ; WO 00/04892 PCTIUS99/13948 -179 R 2 is hydrogen or C 1 -C 6 alkyl, optionally substituted by the following groups: phenyl, substituted phenyl, phenoxy, substituted phenoxy, 0 5 NR 4 R 5 , OR 6 , carboxy, carboxamido, H 2 N-C-HN-, thio, methylthio, indole, imidazole, and phthalimido; R 3 is OH, 0, C 1 -C 6 alkyl, or NHOH; R 4 is hydrogen, CI-C 6 alkyl, or CI-C 6 alkanoyl; R 5 is hydrogen or C 1 -C 6 alkyl; and 10 R 6 is hydrogen, CI-C 6 alkyl, C 1 -C 6 alkanoyl, phenyl, or substituted phenyl, and pharmaceutically acceptable salts and solvates thereof.

17. A method according to Claim 1 wherein the compound employed is selected from (S)- 2 -( 4 '-Bromo-biphenyl-4-sulfonylamino)--3-methyl-butyric 15 acid; (S)-2-(4'-Chloro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-3-Methyl- 2 -( 4 '-nitro-biphenyl-4-sulfonylamino)-butyric acid; (S)-2-(4'-Amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-Cyano-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 20 (S)- 2 -( 3 ', 4 '-Dibromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, sodium salt; (S)-2-(3'-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4'-Bromo-2'-fluoro-biphenyl-4-sulfonylamino)-3-methyl butyric acid, 25 (R)- 2 -( 4 '-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)- 2 -( 4 '-Bromo-biphenyl-4-sulfonylamino)-propionic acid; (S)- 2 -( 4 '-Bromo-biphenyl-4-sulfonylamino)-4-methyl-pentanoic acid; (S)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-methyl-butyric 30 acid; WO 00/04892 PCT/US99/13948 -180 (S)- 2 -(4'-Fluoro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)- 2 -(3'-Fluoro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-3 -Methyl-2-(4'-trifluoromethyl-biphenyl-4-sulfonylamino) butyric acid; 5 2-(4'-Formyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 4'-(l -Carboxy- 2 -methyl-propylsulfamoyl)-biphenyl-4-carboxylic acid; 2 -( 4 '-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 10 2 -( 4 '-AminomethYl-biphenyl-4-sulfonvlamino)-3-methyl-butyric acid; (S)-2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid; (S)-(4'-Isopropyl-biphenyl-4-su I fony 1 amino)-3-Phenyl-propionic 15 acid; (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; and (S)-2-(4'-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert.-butyl ester. 20

18. A method according to Claim 1 utilizing a compound of the formula O 0 || || R I-X-S-N-C-Y-R 2 11 1 25 OR or a pharmaceutically acceptable salt thereof wherein: X and Y are selected from oxygen, sulfur and (CR'R")n wherein n is an integer of from I to 4 and R' and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, 30 phenyl optionally substituted or R' and R" together form a spirocycloalkyl or a carbonyl; WO 00/04892 PCT/US99/13948 -181 R is hydrogen, a straight or branched alkyl of from I to 8 carbon atoms or benzyl; RI and R 2 are each independently selected from (a) phenyl or phenoxy each of which is unsubstituted or is substituted 5 with 1 to 5 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from 1 to 6 carbon atoms and 10 which is straight or branched; phenoxy, hydroxy, fluorine, chlorine, 15 bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and 20 is straight or branched, -(CH 2 )pNR 3 R 4 wherein p is zero or one, and each of R 3 and R 4 is selected from hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms; (b) 1- or 2-naphthyl unsubstituted or substituted with from 1 to 25 3 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from I to 6 carbon atoms and 30 which is straight or branched; hydroxy, phenoxy, WO 00/04892 PCT/US99/13948 -182 fluorine, chlorine, bromine, nitro, 5 trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from I to 4 carbon atoms and is straight or branched, -(CH 2 )pNR 3 R 4 wherein p, R 3 and R 4 have the meanings 10 defined above; (c) arylalkyl; (d) a straight or branched alkyl chain having from 1 to 20 carbon atoms and which is saturated or contains from 1 to 3 double bonds; or 15 (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms.

19. A compound of Claim 14 wherein R 1 is phenyl.

20. A compound of Claim 14 wherein R I is phenyl disubstituted in the 2,6-positions. 20

21. A compound of Claim 14 wherein R 2 is phenyl.

22. A compound of Claim 14 wherein R 2 is phenyl disubstituted in the 2,6-positions.

23. A compound of Claim 14 wherein each of R 1 and R 2 is phenyl.

24. A compound of Claim 16 wherein each phenyl is disubstituted in the 25 2,6-positions. WO 00/04892 PCT/US99/13948 -183

25. A compound of Claim 14 wherein R 1 is phenyl disubstituted in the 2,6-positions and R 2 is phenyl trisubstituted in the 2,4,6-positions.

26. A compound of Claim 14 wherein R 1 is 2,6-bis(1-methylethyl)phenyl and R 2 is 2,6-bis(I -methylethyl)phenyl or 2,4,6-tris(1 -methylethyl)phenyl. 5

27. A compound of Claim 14 wherein R 1 is phenyl or isophenyl disubstituted in the 2,6-positions, wherein R 2 is phenyl or is phenyl disubstituted in the 2,6-positions, wherein each of RI and R 2 is phenyl, wherein each phenyl is disubstituted in the 2,6-position, wherein R 1 is phenyl disubstituted in the 2,6-positions and R 2 is phenyl trisubstituted in the 2 , 4 , 6 -positions, 10 wherein R 1 is 2,6-bis(1-methylethyl)phenyl and R 2 is 2,6-bis(1 methylethyl)phenyl or 2,4,6-tris(1 -methylelthyl)phenyl, wherein one of R 1 and R 2 is the group R 5 15 -(CH 2 )t-C-(CH 2 )w-R 7 R 6 wherein t is zero or 1 to 4; w is zero or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R 5 and R 6 are each independently selected 20 from hydrogen or alkyl having from 1 to 6 carbon atoms, or when R 5 is hydrogen, R 6 can be selected from the groups defined for R 7 ; and R 7 is phenyl or phenyl substituted with from 1 to 3 substituents selected from a straight or branched alkyl group having from I to 6 carbon atoms, straight or branched alkoxy group having from I to 6 carbon atoms, phenoxy, 25 hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, COOalkyl wherein alkyl has from I to 4 carbon atoms, or -(CH 2 )pNR 3 R 4 wherein P, R 3 and R 4 have the meanings defined above.

28. A compound according to Claim 14 wherein WO 00/04892 PCTIUS99/13948 -184 X is oxygen, sulfur or (CR'R")n; Y is oxygen, sulfur or (CR'R")n with the proviso that at least one of X or Y is (CR'R")n wherein n is an integer of from I to 4 and R' and R" are each independently hydrogen, straight or branched alkyl of 5 from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R" taken together form a carbonyl or a spirocycloalkyl group of from 3 to 10 carbons; R is hydrogen; R 1 is phenyl optionally substituted, straight or branched alkyl of from I to 10 10 carbon atoms, cycloalkyl of from 3 to 10 carbon atoms; R 2 is phenyl optionally substituted, straight or branched alkyl of from I to 10 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenoxy optionally substituted.

29. A compound according to Claim 14 wherein 15 X is oxygen; Y is (CR'R")n wherein n is an integer of from I to 2; R is hydrogen; R 1 is optionally substituted phenyl; R 2 is optionally substituted phenyl or phenoxy, straight or branched alkyl 20 of from I to 10 carbons, or cycloalkyl of from 3 to 10 carbons; R' and R" are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R" taken together form a carbonyl or a spirocycloalkyl. 25

30. A compound according to Claim 14 sulfamic acid[[2,4,6-tris(1-methyl ethyl)phenyl]acetyl-2,6-bis(I-methylethyl)phenyl ester.

31. A compound of Claim 14 selected from: Sulfamic acid (phenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, WO 00/04892 PCT/US99/13948 -185 Sulfamic acid[[2,6-bis(1-methylethyl)phenyl]acetyl]-2,6 bis(1-methylethyl)phenyl ester, Sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl-2,4,6 tris(1 -methylethyl)phenyl ester, 5 Sulfamic acid[[2,6-bis(1-methylethyl)phenyl]acetyl]-2,4,6 tris(1 -methylethyl)phenyl ester, Sulfamic acid[adamantaneacetyl] -2,6-bis [1 -methylethyl)phenyl ester, Sulfamic acid[[2,6-bis(1 -methylethyl)phenyl]acetyl] 10 2,6-bis(1-methylethyl)phenyl ester-sodium salt, Sulfamic acid[[2,4,6-tris(I -methylethyl)phenyl]acetyl] 2,6-bis(I -methylethyl)phenyl ester-sodium salt, Sulfamic acid (decanoyl)-2,6-bis-(1-methylethyl)phenyl ester, Sulfamic acid (dodecanoyl)-2,6-bis-(1 -methylethyl)phenyl ester, 15 2,6-Bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl] methyl]sulfonyl]benzeneacetamide, 2,6-Bis(I -methylethyl)-N-[[[2,4,6-tris(1 -methylethyl)phenyl] methyl]sulfonyl]benzeneacetamide-sodium salt, 2,6-Bis(1 -methylethyl)phenyl [ [ [ 2 ,4,6-tris(I -methylethyl)phenyl] 20 methyl]sulfonyl]carbamate, 2,6-Bis(1 -methylethyl)phenyl [ [ [2,4,6-tris(I -methylethyl)phenyl] methyl]sulfonyl]carbamate-sodium salt, Sulfamic acid (1-oxo-3,3-diphenylpropyl)-2,6-bis(1 methylethyl)phenyl ester, 25 Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis( 1 methylethyl)phenyl ester, Sulfamic acid trans- [(2-phenylcyclopropyl)carbonyl] -2,6-bis(1 30 methylethyl)phenyl ester, Sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, WO 00/04892 PCT/US99/13948 -186 Sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, Sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, 5 Sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(I -methylethyl)phenyl ester, Sulfamic acid [3-thiophenyl(acetyl)]-2,6-bis(I-methylethyl)phenyl ester, Sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(1 10 methylethyl)phenyl ester, Sulfamic acid (oxophenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [2-trifluoromethylphenyl(acetyl)]-2,6-bis(1 methylethyl)phenyl ester, 15 Sulfamic acid (1 -oxo-2-phenylpropyl)-2,6-bis( 1 methylethyl)phenyl ester, Sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(1 methylethyl)phenyl ester, Sulfamic acid (cyclohexylacetyl)-2,6-bis(1 -methylethyl)phenyl 20 ester, Sulfamic acid (diphenylacetyl)-2,6-bis(1 -methylethyl)phenyl ester, Sulfamic acid (triphenylacetyl)-2,6-bis(I -methylethyl)phenyl ester, Sulfamic acid [(1-phenylcyclopentyl)carbonyl]-2,6-bis(1 methylethyl)phenyl ester, 25 Sulfamic acid (3-methyl-I -oxo-2-phenylpentyl)-2,6-bis(1 methylethyl)phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl)-2,6-bis(I-methylethyl)phenyl ester, Sulfamic acid (cyclohexylphenylacetyl)-2,6-bis(I 30 methylethyl)phenyl ester, Sulfamic acid (I -oxo-2,2-diphenylpropyl)-2,6-bis(I methylethyl)phenyl ester, WO 00/04892 PCT/US99/13948 -187 Sulfamic acid [(9H-fluoren-9-yl)carbonyl]-2,6-bis( 1 methylethyl)phenyl ester, Sulfamic acid (1-oxo-3-phenylpropyl)-2,6-bis(1 methylethyl)phenyl ester, 5 Sulfamic acid [1-oxo-3-[2,4,6-tris(1-methylethyl)phenyl] 2-propenyl]-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [1-oxo-3-[2,4,6-tris(1-methylethyl)phenyl]propyl] 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [(acetyloxy)[2,4,6-tris(1-methylethyl)phenyl]acetyl] 10 2,6-bis(I-methylethyl)phenyl ester, Sulfamic acid [hydroxy[2,4,6-tris(1-methylethyl)phenyl]acetyl] 2,6-bis(I -methylethyl)phenyl ester, Sulfamic acid [fluoro[2,4,6-tris(I-methylethyl)phenyl]acetyl] 2,6-bis(1-methylethyl)phenyl ester, 15 Sulfamic acid (3-methyl-i -oxo-2-phenylpentyl)-2,6-bis(1 methylethyl)phenyl ester sodium salt, Sulfamic acid [[2,4,6-tris(1-methylethyl)phenoxy]acetyl] 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [[2,6-bis(1-methylethyl)phenoxy]acetyl]-2,6-bis 20 (1-methylethyl)phenyl ester, and Sulfamic acid [[2,4,6-tris(I-methylethyl)phenyl]acetyl] 2,6-bis(phenyl)phenyl ester.

32. A method according to Claim I wherein the MMP inhibitor is selected from 25 Br c 0 SO 2 N CO 2 H and WO 00/04892 PCTIUS99/13948 -188 0 SO 2 NH CO 2 H and the ACAT inhibitor is selected from [(2,4,6-triisopropyl-phenyl) acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester and N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl 5 acetamide are administered.

33. A pharmaceutical composition for treating and/or preventing atherosclerotic lesions comprising a therapeutically effective amount of an ACAT inhibitor and a MMP inhibitor.

34. A method according to Claim 1 wherein the MMP inhibitor is selected 10 from Br - / \ / SO 2 N CO 2 H and O SO 2 NH CO 2 H and the ACAT inhibitor is selected from [(2,4,6-triisopropyl-phenyl) 15 acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester and N-( 2 ,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl acetamide are administered.

35. A method according to Claim 1 wherein the ACAT inhibitor is selected from: 20 4-Hexadecylamino-benzoic acid monosodium salt; 3,5-Dimethyl-1-[5-(1,4,5-triphenyl-2H-imidazol-2-ylsulfanyl) pentyl]-1H-pyrazole monosodium salt; WO 00/04892 PCT/US99/13948 -189 8-(1,4,5-Triphenyl-2H-imidazol-2-yloxy)-octanoic acid; 9-Bromo-6,11-dihydro-dibenzo[b,e]oxepine- 11 -carboxylic acid (2,6-diisopropyl-phenyl)-amide; 5-((3,5-Di-tert-butyl-4-hydroxy-phenylamino)- { [4-(2,2-dimethyl 5 propyl)-benzyl]-hexyl-amino}-methylene)-2,2-dimethyl-[1,3]dioxane 4,6-dione; 3-(2,4-Difluoro-phenyl)-1-[ 4 -(2,2-dimethyl-propyl)-benzyl] I -heptyl-urea; I -Heptyl- 1-[4-(3-methyl-butyl)-benzyl]-3-(2,4,6-trifluoro-phenyl) 10 urea; 3-(2,4-Difluoro-phenyl)- I -[5-(4,5-diphenyl- 1 H-imidazol 2-ylsulfanyl)-pentyl]- 1 -heptyl-urea; I -Butyl-3- {2-[3-(5-ethyl-4-phenyl-imidazol- I -yl)-propoxy] 6-methyl-phenyl } -urea; 15 1-(2-{2- [4-(2,2-Dimethyl-propyl)-phenyl]-ethyl } -4,6-difluoro phenyl)-3-heptyl-urea; Octadeca-9,12-dienoic acid (1 -phenyl-ethyl)-amide; 3-(1H-Indol-3-yl)-2-octadec-9-enoylamino-propionic acid ethyl ester; 20 3-(Dimethyl-nonyl-silanyl)-N-(1 -phenyl-2-p-tolyl-ethyl) propionamide; (R)2-Hexyl-decanoic acid (6-methyl-2,4-bis-methylsulfanyl pyridin-3-yl)-amide; N-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-ethyl]-4-fluoro 25 benzenesulfonamide; 2-(2-Ethoxy-ethylsulfanyl)-4,5-diphenyl- 1 H-imidazole; 4-Cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyl 4,5-dihydro-3H-imidazol-4-yl]-N-methyl-benzamide; - { 3-[3-(1-Methyl-1 H-imidazol-2-yl)-2-phenethyl-2H-chromen 30 6-yloxy]-propyl}-cyclopentanecarboxylic acid ethyl ester; 1-[4-(2-Chloro-phenyl)-2-ethyl-thieno[2,3-b]pyridin-5-yl] 3-(2,4-difluoro-phenyl)-urea; WO 00/04892 PCT/US99/13948 -190 1-(2-Cyclohexyl-[1,3]dithiolan-2-ylmethyl)-3-(2,6-diisopropyl phenyl)-urea; 1 -Cycloheptyl- 1 -(2,3-dihydro-benzo[ 1,4]dioxin-5-ylmethyl) 3-(2,4,6-trimethyl-phenyl)-urea; 5 1- {2- [4-(1,2-Dimethoxy-ethoxy)-phenyl] -ethyl } -3-(2,4-dimethoxy phenyl)- I -heptyl-urea; 2-(4- {2- [3 -(2,4-Dimethoxy-phenyl)- 1 -heptyl-ureido] -ethyl} phenoxy)-2-methyl-propionic acid; 3-(2,4-Difluoro-phenyl)-1-octyl-1-(2,3,4,5-tetrahydro 10 benzo[b]oxepin-5-yl)-urea; N-( 2 , 6 -Diisopropyl-phenyl)-2-octadecylsulfanyl-acetamide; 2-Bromo-6, 11 -dihydro-dibenzo[b,e]oxepine- II -carboxylic acid (2,6-diisopropyl-phenyl)-amide; (±)N-(1, 2 -Diphenyl-ethyl)-3-(2-heptyloxy-phenyl)-propionamide; 15 2,2-Dimethyl-dodecanoic acid (7-methoxy-4-oxo-chroman-8-yl) amide; (Z) 1 -(6,7-Dimethoxy-3,4-dihydro- 1 H-isoquinolin-2-yl)-octadec 9-en-I -one; (Z)2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid 20 [2-(2-octadec-9-enoylamino-ethylcarbamoyl)-ethyl]-amide; 1-Benzyl-I-(5-methyl-3-phenyl-benzofuran-2-ylmethyl) 3-(2,4,6-trifluoro-phenyl)-urea; 5-Chloro-3-o-tolyl-benzofuran-2-carboxylic acid (2,6-diisopropyl phenyl)-amide; 25 2-(2,4a-Dimethyl-4a,5-dihydro-naphthalen- I -ylsulfanyl)-N {2-[(6,6-dimethyl-hepta-2,4-diynyl)-pentyl-amino] -ethyl } -acetamide; (Z)Octadec-9-enoic acid [2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl) I -phenyl-ethyl]-amide; N-( 4 -Dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl) 30 4-(phenyl-propyl-amino)-butyramide; (Z) I -(6,7-Dimethoxy-3-phenyl-3,4-dihydro- I H-isoquinolin-2-yl) octadec-9-en- I -one; WO 00/04892 PCT/US99/13948 -191 (trans) 1,4-Bis-(4-methoxy-phenyl)-3-(3-phenyl-propyl)-azetidin 2-one; I -Butyl-3-{2-dimethylamino-6-[3-(4-phenyl-imidazol- 1-yl) propoxy]-phenyl}-urea; 5 1-{ 2-Dimethylamino-6-[3-(4-phenyl-imidazol- 1 -yl)-propoxy] phenyl } -3 -pentyl-urea; 1- {2-Dimethylamino-6-[3-(5-methyl-4-phenyl-imidazol- 1-yl) propoxy] -phenyl } -3 -pentyl-urea; 1-(2- {2-[4-(2,2-Dimethyl-propyl)-phenyl]-ethyl } -4,6-difluoro 10 phenyl)-3-heptyl-urea; (4S-trans)6-(4,5-Diphenyl- 1 H-imidazol-2-ylsulfanylmethyl) 4-hydroxy-4-methyl-tetrahydro-pyran-2-one; 2-(3-[1,3]Dioxan-2-yl-propylsulfanyl)-4,5-diphenyl- I H-imidazole; Hydroxy-phenyl-acetic acid 3,3,5-trimethyl-cyclohexyl ester; 15 Acetic acid 1 -(11 -hydroxy-4-methoxy-9-methyl-5-oxo-5H,7H 6,12-dioxa-dibenzo[a,d]-cycloocten-3-yl)-3-methyl-butyl ester; I 0-Hydroxy-2,4a,6a,6b,9,10,1 2 a-heptamethyl-4-octadecanoyloxy 1,2,3,4,4a,5,6, 6a,6b,7,8,8a,9,10, 11,12,12a,12b,13,14b-eicosahydro picene-2-carboxylic acid; 20 3-[(2,2,5,5-Tetramethyl-[1,3]dioxane-4-carbonyl)-amino] propionic acid 2-[3-(2,2-dimethyl-propyl)-3-nonyl-ureido]-cyclohexyl ester; 1-(2,6-Diisopropyl-phenyl)-3-( 2 -p-tolyl-heptyl)-urea; 1-[4-(2-Chloro-phenyl)-6,8-dimethyl-quinolin-3-yl]-3-(2,4 25 difluoro-phenyl)-urea; 1-[4-(2-Chloro-phenyl)- 1,6,7-trimethyl-2-oxo- 1,2-dihydro quinolin-3-yl]-3-(2,4-difluoro-phenyl)-urea; 1-[4-(2-Chloro-phenyl)-6,7-dimethy-2-oxo-2H-chromen-3-yl] 3-(2,4-difluoro-phenyl)-urea; 30 (S) 1 -[6-Bromo-5-(2-chloro-phenyl)- 1,3-dimethyl-2-oxo 2,3-dihydro- 1 H-benzo[e] [1,4]-diazepin-7-yl]-3-(2-hydroxy 1 -hydroxymethyl- I -methyl-ethyl)-urea; WO 00/04892 PCTIUS99/13948 -192 3-(4,5-Diphenyl- I H-imidazol-2-ylsulfanylmethyl)- 1-methyl piperidine; 2-(5,5-Dimethyl-[ 1,3]dioxan-2-yl)-4,5-diphenyl- 1 H-imidazole; 2,2-Dimethyl-5-[3-(1-methyl-I H-imidazol-2-yl)-2-propyl 5 chroman-6-yloxy]-pentanoic acid ethyl ester; N-(4-Hexadecylamino-benzoyl)-4-methyl-benzenesulfonamide; 2 -( 4 -Chloro-phenyl)-6-cyclohexyl-4-(2-oxo-2-phenyl-ethyl) 6,7-dihydro-4H- 1,4,6,8a-tetraaza-s-indacene-5,8-dione; [2-(3-tert-Butyl-4-hydroxy-naphthalen- 1 -yl)- 1 -(diethoxy 10 phosphoryl)-vinyl]-phosphonic acid diethyl ester; 5-[1 -(acetyloxy)-3-methylbutyl]-2'-(hydroxymethyl)-4-methoxy 4'-methylspiro[benzofiran-2(3H), 1'-cyclohexa-2',4'-diene]-3,6'-dione; 5-[1 -(acetyloxy)-3-methylbutyl]-4-methoxy-4'-methyl 3,6-dioxospiro[benzofuran-2(3H), I'-cyclohexa-2',4'-diene]-2' 15 carboxaldehyde; (3a,4a,22x,24x)-3-hydroxy-22-[(1 -oxooctadecyl)oxy]-24-norolean 12-en-29-oic acid; 1-[5-(4,5-Diphenyl-IH-imidazole-2-sulfinyl)-pentyl]-3,5-dimethyl 1H-pyrazole; and 20 N-butyl-3-[[(4-decyloxyphenyl)carbonyl]-amino]-4-(methylthio) benzamide.

36. A method according to Claim I wherein the MMP inhibitor is selected from: 4 -[ 2 -( 2 -Carboxymethyl-4-phenyl-butylamino)-3-cyclohexyl 25 propionylamino]benzoic acid methyl ester; 4 -[ 2 -( 2 -Carboxymethyl-4-phenyl-butyrylamino)-3,3-methyl butyrylamino]-benzoic acid methyl ester; 4 -[ 2 -( 2 -Carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl butyrylamino]-benzoic acid methyl ester; 30 4 -[ 2 -( 2 -Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3 dimethyl-butyrylamino]-benzoic acid methyl ester; WO 00/04892 PCTIUS99/13948 -193 4-[2-(2-Carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl butyrylamino]-benzoic acid methyl ester; 4 -[ 2 -( 2 -Hydroxaminocarbonylmethyl-5-methyl-valerylamino)-3,3 dimethyl-butyrylamino]-benzoic acid methyl ester; 5 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-2 cyclohexylpropionylamino]benzoic acid methyl ester; 4 -[ 2 -(2-Carboxymethyl-4-methyl-valerylamino)-4-methyl valerylamino]-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-phenyl-valerylamino)-3,3-dimethyl 10 butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-pentanoylamino)-3-(1H-indol-3 yl)-propionylamino-benzoic acid methyl ester; 5-Methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0 13,18]nonadeca 12(19),13,15,17-tetraen- I 0-ylcarbamoyl)-hexanoic acid; 15 4 -[ 2 -( 2 -Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3 methyl-butyrylamino]-benzoic acid methyl ester; 4-[ 2 -( 2 -Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-2 cyclohexylpropionylamino]-benzoic acid methyl ester benzoic acid methyl ester; 20 4 -[ 2 -( 2 -Hydroxaminocarbonylmethyl-4-methyl-valerylamino)-4 methyl-valerylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butylamino)-3 cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Methoxyaminocarbonylmethyl-4-phenyl-butylamino)-3 25 cyclohexylpropionylamino]benzoic acid methyl ester; 4 -[ 2 -(2-Hydroxaminocarbonylmethyl-5-phenyl-valerylamino)-3,3 dimethyl-butyrylamino]-benzoic acid methyl ester; 5-Methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca 12(19),13,15,17-tetraen- 1 0-ylcarbamoyl)- I -hexylhydroxamic acid; 30 4-[ 2 -( 2 -Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino) 3-(IH-indol-3-yl)-propionylamino-benzoic acid methyl ester; 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl-1-phenylcarbamoyl propylcarbamoyl]-5-methyl-hexanoic acid; WO 00/04892 PCT/US99/13948 -194 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl- I -phenylcarbamoyl propylcarbamoyl]-5-methyl-hexanoic acid N-hydroxyamide; 4-[ 2 -( 2 -Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino) 2-cyclohexyl-acetylamino]-benzoic acid methyl ester; 5 2-(Phenyl-2-ethyl)benzoic acid N-hydroxy amide; 4-[ 2 -(2-Acylhyrdazinomethyl-4-methyl-pentanoylamino)-3-(1H indol-3-yl)-propionylamino]-benzoic acid methyl ester; 2-(Propylthio)-pyridine-3-N-(hydroxy)carboxamide; 4-[2-(2-Carboxymethyl-5-phenyl-pentanoylamino)-2 10 cyclohexylacetylamino]benzoic acid methyl ester; [4-(N-Hydroxyamino)-2R-isobutyl-3S-((thien-2 ylthio)methyl)succinyl]-L-phenylalanine-N-methylamide; N-Hydroxy-5-phenylpentanamide; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-valeroyl)amino)-4 15 methyl-valeroyl]aminobenzoic acid methyl ester; 4-[ 2 -( 2 -Carboxymethyl-5-(3-hydroxyphenyl)-4-pentenoyl)amino) 4 -methyl-valeroyl]aminobenzoic acid methyl ester; 4-[ 2 -( 2 -Carboxymethyl-5-(3-aminophenyl)-4-pentenoyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester, trifluoroacetate salt; 20 2 -(Phenyl-2-ethyl)pyridine-3-N-hydroxycarboxamide; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 25 4 -[ 2 -( 2 -Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 2-[3-(3-Hydroxy-phenyl)-propyl]-benzohydroxamic acid; 2-(Thiobenzyl)benzoic acid N-hydroxy amide; 1-(3-Phenyl-propyl)-pyrrolidine-2-hydroxamic acid; 30 4 -[ 2 -( 2 -Carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; WO 00/04892 PCT/US99/13948 -195 4-[ 2 -( 2 -Carboxymethyl-5-(N'-methylureido)valeroyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 4 -[ 2 -( 2 -Carboxymethyl-5-(triflouroacetamido)valeroyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 5 4 -[ 2 -( 2 -Carboxymethyl-2-phenylacetylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4 -[ 2 -( 2 -Hydroxaminocarbonylmethyl-2-phenylacetylamino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 4 -[ 2 -( 2 -Carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl 10 acetylamino]-benzoic acid methyl ester; 2-[3-(3-Amino-phenyl)-propyl]-benzohydroxamic acid; cis- 4 -Benzyloxy-pyrrolidine-2-carboxylic acid; 4-[2-(2-Carboxymethyl-5-(3-amino-4-(triflouromethyl)phenyl) valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; 15 4 -[ 2 -( 2 -Carboxymethyl-5-(methanesulfamido)valeroyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; N-Cbz-L-Tyrosine; N-Boc-L-Tryptophan; 4-[ 2 -(Carboxy-2-o-tolyl-propionylamino-4-methyl 20 pentanoylamino]-benzoic acid methyl ester; 4 -[ 2 -(Carboxymethyl-hepanoylamino)-4-methyl-pentanoylamino] benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 25 4-[ 2 -( 2 -Carboxymethyl-5-(4-n-butylphenyl)-4-pentenoyl)amino)-4 methyl-valeroyl]aminobenzoic acid methyl ester; 4 -[ 2 -( 2 -Carboxymethyl-2-(2-thienyl)acetylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-(3-aminophenyl)-butyryl)amino)-4 30 methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(biphen-4-yl)-valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; WO 00/04892 PCT/US99/13948 -196 cis-4-Benzylsulfanyl-pyrrolidine-2-carboxylic acid; 2-Cyclohexylmethyl sulfonyl-benzoic acid; Pyrrolidine-1-carbothioic acid phenethyl-amide; 3-(2-Methyl-thiazol-4-yl)-N-phenethyl-propionamide; 5 N-Phenyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-IH-imidazol-4 yl]-propionamide; 3-( 3 H-Imidazol-4-yl)-N-phenethyl-propionamide; 4-[ 2 -( 2 -Carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 10 2-Cyclohexylmethyl sulfonyl-benzohydroxamic acid; [2-Oxo-3 -(3 -phenyl-propyl)-tetrahydro-furan-3-yl] -acetic acid; 4-[2-(2-Carboxymethyl-5-(fluoren-2-yl)valeroyl)amino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 4-[ 2 -( 2 -Carboxymethyl-2-(3-thienyl)acetylamino)-4-methyl 15 valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Benzylthio-3-carboxy-propionylamino)-4 methylpentanoylamino]-benzoic acid methyl ester; 4-[ 2 -( 2 -Carboxymethyl-4-(2-indolyl)butyrylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 20 1 -Allyl-3-(2-hydroxyethyl)-2-thiourea; 3-(1 -Hydroxyimino-propyl)-6-phenyl-hexanoic acid; 2-(3H-Imidazol-4-ylmethyl)-N I,N 4 -diphenethyl-succinamide; 3-( 2 -Hydroxymethyl-3H-imidazol-4-yl)-N-phenethyl propionamide; 25 6-Phenyl-3-propionyl-hexanoic acid; 4- { 2 -([ 2 -Hydroxyamino-2-hydroxyimino-ethyl]-5-phenyl pentanoylamino)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 4-[ 2 -( 2 -( 2 -Phenylcyclopropyl)succinylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 30 6-Biphenyl-4-yl-[2,2-dimethyl- I -(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid trifluoroacetate salt; WO 00/04892 PCT/US99/13948 -197 3-[I-(5,6-Dichloro- I H-benzoimidazol-2-yl)-3-methyl butylcarbamoyl]-5-methyl-hexanoic acid; 6-Biphenyl-4-yl-3-[1-(5,6-dichloro- I H-benzoimidazol-2-yl)-3 methyl-butylcarbamoyl]-5-methyl-hexanoic acid; 5 2 -Carboxymethyl-heptanoyl-2-(N-methylcarboxamide)piperidine; 4-[ 2 -( 2 -( 2 -Phenylcyclopropyl)succinylamino)-4-methyl valeroyl]aminobenzoic acid methyl ester; 2-Carboxymethyl-heptanoyl-3-(N-methylcarboxamide) hexahydropyridazine; 10 6-Biphenyl-4-yl-3-[1-[3-(3-hydroxy-ethyl)-phenylcarbamoyl]-2,2 dimethyl-propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5 methyl-3S-hexyl)succinamide; 6-Biphenyl-4-yl-3-[1-[3-( 2 -aminoethyl)-phenylcarbamoyl]-2,2 15 dimethyl-propylcarbamoyl]-hexanoic acid; 2 R-( 3 -( 4 -Biphenyl)propyl)-N-(diphenylmethyl)succinamide; 2 R-( 3 -( 4 -Biphenyl)propyl)-N-(phenylmethyl)succinamide; 2 -( 2 -Oxo-imidazolidin-4-ylmethyl)-5-phenyl-pentanoic acid; 2-(3-Biphenyl-4-yl-propyl)-NI-[1-(5,6-dichloro-1H 20 benzoimidazol-2-yl)-3-methyl-butyl]-N 4 -hydroxy-succinamide hexanoic acid; 6-Biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid, N-hydroxyamide; 2R-(3-(4-Biphenyl)propyl)-N-((1 -hydroxy-1 25 methylethyl)phenylmethyl)succinamide; 6-Biphenyl-4-yl-3 -[1 -phenylcarbamoyl-2-(4-cyano benzylsulfanyl)-2-methyl-propylcarbamoyl]-hexanoic acid; 4-f{2-[2-Carboxymethyl-5-(4'-hydroxy-biphenyl-4-yl) pentanoylamino]- 4 -methyl-pentanoylamino}-benzoic acid methyl ester; 30 1 -(N-Methyl-N-phenethylthiocarbomyl)-pyrrolidine-2-carboxylic acid; WO 00/04892 PCT/US99/13948 -198 6-Biphenyl-4-yl-3-({ cyclohexyl-[2-(4-sulfanoyl-phenyl) ethylcarbamoyl]-methyl}-carbamoyl)-hexanoic acid; 3R(6-(4-Biphenyl)-3-(N-benzylcarbamoyl))-hexanoic acid N-hydroxyamide; 5 [3 -(3-Biphenyl-4-yl-propyl)-2-oxo-pyrrolidin-3 -yl]-acetic acid; 2-Benzylsulfonyl-cyclopent- 1 -ene-carboxylic acid hydroxamide; [ 2 -Oxo- 3 -( 3 -phenyl-propyl)-pyrrolidin-3-yl]-acetic acid; [3 -(3 -Naphthalen-2-yl-propyl)-2-oxo-pyrrolidin-3 -yl] -acetic acid; 2-Benzylsulfonyl-cyclohex- I -enecarboxylic acid hydroxy amide; 10 6-Benzylsulfonyl-cyclohex- I -enecarboxylic acid hydroxy amide; 2R-(3-(4-Biphenyl)propyl)-N-(3-methylpyridine)succinamide; { 3-[3-(3-Hydroxy-phenyl)-propyl]-2-oxo-pyrrolidin-3-yl } -acetic acid; 6-Biphenyl-4-yl-{ [cyclohexyl-(3-morpholin-4-yl 15 propylcarbamoyl)-methyl]-carbamoyl}hexanoic acid; [2-Oxo-3-(3-biphenyl-propyl)-tetrahydro-furan-3-yl] -acetic acid; 4 -[ 2 -( 2 -Thioamidomethyl-5-phenyl-valerylamino)-4-methyl valeroylamino]-benzoic acid methyl ester; 4 -[ 2 -( 2 -Amino-2-hydroxyimino-ethyl-5-phenyl-valerylamino)-4 20 methyl-valeroylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl- I -(4-methylsulfamoyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(2-hydroxyethylsulfamoyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 25 1 -(N-Hydroxy)-3-(2-bibenzyl)urea; 4-(2-{5-[7-( 2 -Amino-acetylamino)-9H-fluoren-2-yl]-2 carboxymethyl-pentanoylamino}- 4 -methyl-pentanoylamino)-benzoic acid methyl ester TFA salt; 3R-( 6 -( 4 -Biphenyl)propyl)-N-(3-methylpyridinecarbamoyl) 30 hexanoic acid N-hydroxy amide; 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl) phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid; WO 00/04892 PCT/US99/13948 -199 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino ethylsulfamoyl)-phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid, trifluoroacetate salt; 4-(2-{ 2-Carboxymethyl-5-[4-(1H-tetrazol-5-yl)-phenyl] 5 pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-ethyl)-phenyl) pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 4-(2-{ [5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H pyrrole-3 -carbonyl]-amino} -4-methyl-pentanoylamino)benzoic acid 10 methyl ester; 5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3 carboxylic acid(2-cyclohexyl- 1 -methylcarbamoyl-ethyl)amide; 6-Biphenyl-4-yl-3-[2,2-dimethyl-I -(4-(3-morpholin-4-yl sulfamoyl)-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 15 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfanyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfonyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4 -[ 2 -(5-Biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-pent-4 20 enoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfinyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-(2-{[5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3 carbonyl]-amino } -4-methyl-pentanoylamino)benzoic acid methyl ester; 25 5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3 carboxylic acid(2-cyclohexyl- 1 -methylcarbamoyl-ethyl)amide; 6-Biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-cyano-biphenyl-4-yl) 30 pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy-1-(S)-phenyl-ethylcarbamoyl) hexanoic acid; WO 00/04892 PCT/US99/13948 -200 3-(R)-(1 -(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy- I -hydroxymethyl ethylcarbomyl)-hexanoic acid; 5 4-[2-(2-Carboxymethyl-5-(4-pyridin-4-yl-phenyl) pentanoylamino)-4-methyl-pentanoylamino]benzoic acid methyl ester; 6-Biphenyl-4-yl(2-hydroxy-2-methyl- I -phenylcarbamoyl propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl(2-hydroxy-2-methyl- 1 -phenylcarbamoyl 10 propylcarbamoyl)-hexanoic acid; 3-{2-Allylsufamyl-2-methyl- 1-[2-(4-sulfamoyl-phenyl) ethylcarbamoyl]-propylcarbamoyl}-6-biphenyl-4-yl-hexanoic acid; 4-[ 2 -(5-Biphenyl-4yl-2-carboxymethyl-pentanoylamino)-4,5 dihydroxy-pentanoylamino]-benzoic acid methyl ester; 15 4-(2-{ 5-[ 4 '-(2-Amino-ethoxy)-biphenyl-4-yl]-2-carboxymethyl pentanoylamino } - 4 -methyl-pentanoylamino)-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy- 1-(S)-phenyl-ethylcarbamoyl) hexanehydroxamic acid; 3-(R)-(1 -(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl 20 hexanehydroxamic acid; N-[5-(Biphenyl-4-yl)-2-(N-hydroxyformamido)methylpentanoyl] tert-leucine, N-(pyrid-4-yl)amide; [ 3 -(3-Naphthalen-2-yl-propyl)-2-oxo-tetrahydro-furan-3-yl] -acetic acid; 25 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-I -hydroxymethyl ethylcarbomyl)-hexanehydroxamic acid; 4 -[ 2 -( 2 -Carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4 methyl-pentanoylamino]-benzoic acid methyl ester; 3-[2,2-Dimethyl-I -(pyridin- 4 -ylcarbamoyl)-propylearbamoyl]-5 30 methyl-hexanoicacid; Ni-[2,2-Dimethyl-1 -(pyridin-4-ylcarbamoyl)-propyl]-N4-hydroxy 2-isobutyl-succinamide; WO 00/04892 PCT/US99/13948 -201 4-{2-[2-Carboxymethyl-5-(2-fluoro-biphenyl-4-yl) pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 6-Biphenyl-4-yl-3(R)-(1(S)-hyroxymethyl-2,2-dimethyl propylcarbamoyl)-hexanoic acid; 5 4-{2-[5-Biphen-4-yl-2-(1-carboxy-ethylamino)-pentanoylamino] 4-methyl-pentanoylamino}-benzoic acid methyl ester; 6-Biphenyl-4-yl-3(R)-(1 (S)-hyroxymethyl-2,2-dimethyl propylcarbamoyl)-hexanehydroxamic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfinyl 10 phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 2-(Biphenyl-4-ylsulfonyl)-cyclohex- 1 -enecarboxylic acid hydroxyamide; 6-(Biphenyl-4-ylsulfonyl)-cyclohex- I -enecarboxylic acid hydroxyamide; 15 2-Phenethylsulfanyl-cyclohex- I -enecarboxylic acid hydroxyamide; 6-(4'-cyano-biphenyl-4-yl)-3-[2-hydroxy-1-(4-methylsulfinyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 1-{ 1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid; 20 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4S-methylsulfinyl phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-3,3,3-trifluoropropyl) phenyl)-pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 25 2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 1-{ 1-[i-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl butylcarbamoyl]-3-methyl-butylcarbamoyl}-pyrrolidine-2-carboxylic acid; trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 4 -[ 2 -( 2 -Carboxymethyl-5-(4-(2-methylthiazol-4-yl)phenyl) 30 valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; WO 00/04892 PCT/US99/13948 -202 I -{ 1-[i -( 4 -Methoxycarbonyl-phenylcarbamoyl)-3-methyl butylcarbamoyl]-3-methyl-butylthiocarbamoyl} -pyrrolidine-2-carboxylic acid; 3 -[(Cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl) 5 methyl)-carbamoyl]-6-(4-pyridin-4-yl-phenyl)-hexanoic acid trifluoroacetate salt; trans- 2 -(Biphenyl-4-yl-methylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 6-Biphenyl-4-yl-3-(1-hydroxymethyl-2,2-dimethyl-but-3 10 enylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3 -(1 -hydroxymethyl-2,2-dimethyl-but-3 enylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(1-hydroxymethyl-2-(S)-(1H-imidazol-4 yl)-ethylcarbamoyl)-hexanoic acid; 15 3-(R)-(2-(R)-Benzyloxy- I -(S)-hydroxymethyl-propylcarbamoyl) 6-biphenyl-4-yl-hexanoic acid; 4-[ 4 -Methyl-2-(2-nitromethyl-5-phenyl-pentanoylamino) pentanoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[3-methyl-I-( 4 -(2-hydroxyethylsulfamoyl) 20 phenylcarbamoyl)-butylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3 -(1 -hydroxymethyl-2-phenyl-ethylcarbamoyl) hexanoic acid; N 1 -(1-Benzyl-2-hydroxy-ethyl)-2-(3-biphenyl-4-yl-propyl)-N 4 hydroxy-succinamide; 25 6-Biphenyl-4-yl-3-(R)-(I-hydroxymethyl-2-(S)-(IH-imidazol-4 yl)-ethylcarbamoyl)-hexanehydroxamic acid; N-Hydroxy-2-[2-Oxo-3-( 3 -phenyl-propyl)-tetrahydro-furan-3-yl] acetamide; 4 -[2-(2-Carboxymethyl-5-(2-hydroxy-biphen-4-yl) 30 valeroylamino)-4-methyl-valeroylamino]-benzoic acid methyl ester; N 1 -(2-Benzyloxy-1-hydroxymethyl-propyl)-2-(3-biphenyl-4-yl propyl)-N 4 -hydroxy-succinamide; WO 00/04892 PCT/US99/13948 -203 trans-2-(4-Phenoxy-benzylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 2-(4-Indol- I -yl-benzylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 5 6-Biphenyl-4-yl-3-[2-hydroxy-2-methyl-1-(4S-methylsulfinyl phenylcarbamoyl)-propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro pyran-3-ylcarbamoyl)-hexanoic acid; 5-Biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoic 10 acid{ 1-[4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl]-3-methyl butyl}-amide; 2-(3-Biphenyl-4-yl-propyl)-N 4 -hydroxy-NI -(2,4,5-trihydroxy-6 hydroxymethyl-tetrahydro-pyran-3-yl)-succinamide; 6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro 15 pyran-3-ylcarbamoyl)-hexanoic acid; N-[2,2-Dimethyl-1S-(pyridin-4-ylcarbamoyl)-propyl]-3R thiophen-3-yl-succinamic acid; 4-[2S-(2R-(3-Biphenyl-4-yl-pyrrol- 1 -yl)-3-carboxy propionylamido)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 20 3-(R)-(2-Benzyloxy-phenyl)- I -(S)-hydroxymethyl ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy- 1 -(S)-(4-hydroxy-benzyl) ethylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid; 25 N-[2-(3-(4-biphenyl)propyl)-5,5-difluoro-4-oxopentanoyl)-L-t leucine, N'-4-(methylthio)phenyl amide; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy- 1 -(S)-(4-hydroxy-benzyl) ethylcarbamoyl)-hexanehydroxamic acid; 4-{2-[2-carboxymethyl-5-(4'-sulfamoyl-biphenyl-4-yl) 30 pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexane carboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -204 3-Acetyl-6-biphenyl-4-yl-3-hexanoic acid; N-[5-(Biphen-4-yl)-2-(1 -carboxy-2-hydroxybut- I -yl)pentanoyl]-t L-leucine, N'-(4-methylthiophenyl)amide; 6-Biphenyl-4-yl-3-( 2 -Hydroxy-cyclohexylcarbamoyl)-hexanoic 5 acid; 2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-N1 -(2-hydroxy cyclohexyl)-succinamide; 6-Biphenyl-4-yl-3-(1 -hydroxyimino-ethyl)-hexanoic acid hydroxamide; 10 6 -Biphenyl-4-yl-3-(2-Hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl- 1 -(pyridin-4-ylcarbamoyl) propylcarbamoyl]-hexanoic acid ethyl ester; 2-(3-Biphenyl-4-yl-pyrrol- 1-yl)-3-carboxy-N-(1 -hydroxy-3 15 phenyl-prop-2-yl)-propionamide; N-[5-(Biphen-4-yl)-2-(1 -carboxy-2-hydroxyethyl)pentanoyl]-L-t leucine, N'-(4-methylthiophenyl)amide; 3-(R)-(2-Hydroxy-1 -(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4 (2-methyl-thiazol-4-yl)-phenyl)-hexanoic acid; 20 3-(R)-(2-Hydroxy-1-(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4 (2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid; 5-Biphenyl-4-yl-2-(1 -hydroxymethyl-3-methylsulfanyl propylcarbamoyl)-pentanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N-hydroxy-N'-(1-hydroxymethyl-3 25 methylsulfanyl-propyl)malonamide; 6-Biphenyl-4-yl-3-(3 -hydroxy-piperidine- 1 -carbonyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-I -carbonyl)-hexanoic acid-hydroxyamide; 30 1-( 4 -Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; WO 00/04892 PCT/US99/13948 -205 1-[ 4 -Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxyamide; N-(1 -Benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-yl-pyrrol- 1-yl) succinamic acid; 5 N-(I-Benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-yl-pyrrol-1-yl) succinamichydroxamic acid; 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(1 (S)-hydroxymethyl-2,2 dimethyl-propylcarbamoyl)-hexanoic acid; 3-(1-Benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid; 10 N1 -(1 -benzyl-2-hydroxy-ethyl)-N 4 -hydroxy-2-isobutyl succinamide; 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(1 (S)-hydroxymethyl-2,2 dimethyl-propylcarbamoyl)-hexanoic hydroxamic acid; 1-[ 4 -Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic 15 acid; 6-Biphenyl-4-yl-3-(2-hydroxy- I -hydroxmethyl-propylcarbamoyl) hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-cyclohexyl- I -(S)-carbamoyl) hexanoic acid; 20 6-Biphenyl-4-yl-3-(2-hydroxy- I -hydroxmethyl-propylcarbamoyl) hexanoichydroxamic acid; 2S-[(1 S-Benzyl-2-hydroxyethylcarbamoyl)-3R-biphenyl-4-yl pyrrol-1-yl-methyl]-pentanoic acid; 3R-(3-Biphenyl-4-yl-pyrrol- 1 -yl)-N-(2R-hydroxy-cyclohexyl- I R 25 yl)-succinamic acid; 2-(3-Biphenyl-4-yl-pyrrol-1-yl)-3-carboxamate-N-(I-hydroxy-3 phenyl-prop-2-yl)-propionamide; trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid; trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acid 30 hydroxyamide; 6-Biphenyl-4-yl-3-(R)-(1-(S)-hydroxymethyl-2-(3-pyridyl) ethylcarbamoyl)-hexanoic acid; WO 00/04892 PCT/US99/13948 -206 6-Biphenyl-4-yl-2-(S)-hydroxy-3-(R)-(I -hydroxymethyl-2-(S) (1 H-imidazol-4-yl)-ethylcarbamoyl)-hexanoic acid; 1-[ 4 -Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; 5 1-[ 4 -Biphenyl- 4 -yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; 1-( 4 -Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; 6-Biphenyl-4-yl-2S-hydroxy-3R-(I S-hydroxymethyl-3 10 methylsulfanyl-propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(1 -(S)-hydroxymethyl-2-(3-pyridyl) ethylcarbamoyl)-hexanehydroxamic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R-(I S-hydroxymethyl-3 methylsulfanyl-propylcarbamoyl)-hexanoic hydroxmic acid; 15 1-[ 4 -( 4 -Bromo-phenoxy)-benzenesulfonyl]-4-(tert butoxycarbonyl)-piperazine-2-carboxylic acidhydroxyamide; 1-[ 4 -(4-Bromo-phenoxy)-benzenesulfonyl]-piperazine-2 carboxylic acidhydroxyamide; 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-[2-hydroxy-1 S-(IH-imidazol 20 4-yl-methyl)-ethyl]-succinamic acid trifluoroacetate; 3R-(3-Biphenyl-4-yl-pyrrol- 1 -yl)-N-[ 1 S-(methoxy methylcarbamoyl)-3-methyl-butyl]-succinamic acid; N-(1-Acetyl-3-methyl-butyl)-3-(3-biphenyl-4-yl-pyrrol-1-yl) succinamic acid; 25 6-Biphenyl-4-yl-3-(R)-(2-oxo-1-tetrahydrofuran-3-(S) ylcarbamoyl)-hexanoic acid; 3-[2,2-Dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-2 hydroxy-5-methyl-hexanoic acid-hydrochloride salt; N 4 -(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-2, N -dihydroxy-3 30 isobutyl-succinamide; 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanoic acid; WO 00/04892 PCT/US99/13948 -207 N-(1 -Benzyl-2-hydroxy-ethyl)-3 -( 4 -biphenyl-4-yl-pyrazol- 1-yl) succinamic acid; N-(8-Oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.0 12,17]octadeca 11(18),12(17),13,15-tetraen-9R-yl)-3S-(3-phenyl-pyrrol-1-yl)-succinamic 5 acid; 4-Acetyl- I -[ 4 -phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxyamide; 1-(Diphenylphosphinic)-piperidine-2-carboxylic acid hydroxamide; 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-[3S-(2RS-hydroxy-5-methyl) 10 hexyl]-succinamic acid; N-(1-(S)-Benzyl-2-hydroxy-ethyl)-3-(R)-(2-biphenyl-4-yl cyclopropylmethyl)-succinamic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-1-tetrahydrofuran-3-(S) ylcarbamoyl)-hexanehydroxamic acid; 15 1-[ 4 -( 4 -Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2 carboxylic acid N-hydroxyamide; 4-(4-Methoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide; 3-(Diphenylphosphinic)-propanoic acid; 20 3-(Diphenylphosphinic)-propanoic acid hydroxyamide; 4-[2-(2-Carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl) pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 1-[ 4 -( 4 -Chlorophenoxy)benzenesulfonyl]-N-hydroxy-4-(N methylcarbamoyl)piperazine-2-carboxamide; 25 4 -[ 4 -( 4 -Bromo-phenoxy)-benzenesulfonyl]-thiomorpholine-3 carboxylic acid N-hydroxyamide; 3-(3-Biphenyl-4-yl-pyrrol- 1 -yl)-N-(2,2-dimethyl- I methylcarbamoyl-propyl)-succinamic acid; 1-[ 4 -Phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, 30 N-hydroxyamide; 4 [ 4 -Phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxyamide; WO 00/04892 PCT/US99/13948 -208 3-[2-Biphenyl-4-yl-ethylsulfanyl]-tetrahydro-pyran--4-carboxylic acid N-hydroxyamide; 6-Biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid; 1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]piperdine-2-amidoxime; 5 2-(3-Biphenylnitrile-4-yl-pyrrol- I -yl)-3-carboxy-N-(1 -hydroxy-3 phenyl-prop-2-yl)-propionamide; {3-[3-(3-Amino-phenyl)-propyl]-2-oxo-tetrahydro-furan-3-y} acetic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid; 10 5-Biphenylvaleric acid; 1-[4-(Methoxy)-benzenesulfonyl]piperdine-2-amidoxime; 1-[4-Phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylic acid N-hydroxyamide; {3-(3-(3-Methylamino-phenyl)-propyl)-2-oxo-tetrahydro-furan-3 15 yl } -acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3 -(S)-ylcarbamoyl) hexanehydroxamic acid; 4-(1H-Indole-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide; 20 1R-[4-Bromo-phenoxy)-benzenesulfonyl)-N-amino-piperidine-2 carboxamide; 2-(3-Biphenyl-4-yl-propyl)-3, N-4-dihydroxy-N 1 -(I(S) hydroxymethyl-3-methanesulfinyl-propyl)-succinamide; N-(1-Benzyl-2-hydroxy-ethyl)-3-[3-(4'-carbamoyl-biphenyl-4-yl) 25 pyrrol-1 -yl]-succinamic acid; I -(Methyl-phenylphosphinic)-piperidine-2-(R)-carboxylic acid hydroxamide; 4-(4-(4-Chlorophenoxy)benzenesulfonyl)-N-hydroxy-morpholine 3R-carboxamide; 30 2S-[1R-(3-(4'-Cyano-biphenyl-4-yl)-pyrrol-1-yl)-N-(2,2-dimethyl 1 S-hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid; WO 00/04892 PCTIUS99/13948 -209 2(S,R)- { S-Benzyl-2-hydroxyethylcarbamoyl-[3R-(4'-cyano biphenyl-4-yl)-pyrrol-1-yl]-methyl}pentanoic acid; 2S-[3-(Biphenyl-4-yl)-pyrrol-1R-yl-(IS-hydroxymethyl-2,2 dimethyl-propylcarbamoyl)-methyl]-5-hydroxypentanoic acid; 5 1-(1, 3 -Dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 3-[3-(4'-Carbamoyl-biphenyl-4-yl]-pyrrol-1-yl)-N-(1 hydroxymethyl-2,2-dimethyl-propyl)-succinamic acid; 4-Methyl-1-(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R 10 piperazinecarboxamide hydrochloride; 1-[4-Chlorophenoxybenzenesulfonyl]-N-hydroxy-2R piperazinecarboxamide; 2 -( 3 -Phenyl-propylsulfonyl)-cyclohexane carboxylic acid hydroxamide; 15 1-(Pyrolidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 1-(Piperidine-1-sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 4-[4-Bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3 20 carboxylic acid-N-hydroxyamide; 1-[ 4 -( 4 -Methoxy-phenylsulfanyl)-benzenesulfonyl]-piperdine-2 carboxylic acid hydroxyamide; 1-[4-(4-Nitrile-phenoxy)-benzenesulfonyl]-4-(tert butoxycarbonyl)-piperazine-2-carboxylic acid N-hydroxyamide; 25 2S-[3-(Biphenyl-4-yl)-pyrrol-1R-yl-(1S-hydroxymethyl-2,2 dimethyl-propylcarbamoyl)-methyl]-pent-4-enoic acid; 6-Oxo-3-( 4 -phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4 carboxylic acid hydroxamate; 4-(t-Butoxycabonyl)- 1 -(4-(pyridin-2-yl)oxybenzensulfonyl)-N 30 hydroxy-piperazine-2-carboxamide; 4-[(4-Fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3 carboxylic acid-N-hydroxyamide; WO 00/04892 PCT/US99/13948 -210 4 -[ 4 -(Fluoro-phenoxy)-benzenesulfonyl]-oxothiomorpholine-3 carboxylic acid-N-hydroxyamide; N-(2,2-Dimethyl- 1 S-hydroxymethyl-propyl)-3R-[3-(4-pyridin-4 yl-phenyl)-pyrrol-1-yl]-succinamic acid; 5 N-(1 S-Benzyl-2-hydroxy-ethyl)-3 S-(5-biphenyl-4-yl-furan-2-yl) succinamic acid; 4 -( 4 -Butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide; 4-(4-Butoxy-benzenesulfonyl)-1-oxothiomorpholine-3-carboxylic 10 acid hydroxyamide; 1-[ 4 -( 4 -Fluorophenyl)benzenesulfonyl]-4-(tert-butoxycarboxyl) 2R-piperazine-2-carboxylic acid hydroxyamide; 1-((4-(4-Chlorophenyl)-piperazine)- 1 -sulfonyl)-piperidine-2 carboxylic acid hydroxamide; 15 cis- 2 -Phenethylsulfanyl-cyclohexanecarboxylic acid hydroxyamide; N-(2-Hydroxy-I S-phenyl-ethyl)-3R-[3-(4-pyridin-4-yl-phenyl) pyrrol- 1 -yl]-succinamic acid; 1-[4-(4-Fluorophenyl)benzenesulfonyl)-N-hydroxy-2R 20 piperazinecarboxamide hydrochoride; 1-(Diphenylphosphinic)-pyrolidine-2-(R)-carboxylic acid hydroxyamide; N,N- { (Diphenylphosphinic)-(acetic acid-sodium salt) } -hydrazide; N-(1 -Benzyl-2-hydroxy-ethyl)-3-(1 -biphenyl-4-yl-1H-pyrrol-3-yl) 25 succinamic acid; trans- 2 -Phenethylsulfonyl-cyclohexanecarboxylic acid hydroxyamide; 1-[4-(4-Flourophenyl)-piperazine- I -sulfonyl]-piperidine-2 carboxylic acid hydroxamide; 30 1-[ 4 -( 4 -Fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2 carboxylic acid hydroxyamide; 4 -[ 4 -(Bromo-phenoxy)-benzenesulfonyl]-2,2-dimethyl- 1 -oxo thiomorpholine-3-carboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -211 N-(2,2-Dimethyl- I S-methylcarbamoyl-propyl)-3R-(3-phenyl pyrrol-l -yl)-succinamic acid; 3R-(3-Biphenyl-4-yl)-N-(2-hydroxy- I S-hydroxymethyl-2-methyl propyl)-succinamic acid; 5 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acid; 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acid hyroxyamide; I -Phenethylcarbamoyl-pyrrolidine-2(R)-carboxylic acid; R- 4 -[ 4 -(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl- I -oxo 10 thiomorpholine-3-carboxylic acid hydroxyamide; 4-(Ethoxycarbonyl)methyl- I -( 4 -( 4 -chlorophenyl)benzenesulfonyl) N-hydroxy-2R-piperazinecarboxamide hydrochloride; N-(2R-Hydroxy-indan-I R-yl)-3R-[3-(4-pyridin-4-yl-phenyl) pyrrol-1-yl]-succinamic acid; 15 N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[3-(4-pyridin 4-yl-phenyl)-pyrrol-1-yl]-succinamic acid; N-(2,2-Dimethyl-1S-methylcarbamoyl-propyl)-3R-[3-(4-pyridin-4 yl-phenyl-4-yl)-pyrrol-1-yl]-succinamic acid; 1-Phenethylcarbamoyl-pyrrolidine-2-(R)-carboxylic acid 20 hydroxyamide; N-(2,2-Dimethyl-1S-methyl carbamoyl-propyl)-3R-[3-(4-propyl phenyl)-pyrrol- I -yl]-succinamic acid; 1-(4-Benzyl-piperazine- I -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 25 3(S)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2 dimethyl-tetrahydro-2H- 1,4-thiazine-3 -carboxamide; 2(R)-4-Methyl- 1 -( 4 -( 4 -fluorophenyl)benzenesulfonyl)-N-hydroxy piperazine-2-carboxamide; N-(2,2-Dimethyl- 1 -methylcarbamoyl-propyl)-3-(5-biphenyl-4-yl 30 furan-2-yl)-succinamic acid; N-(2,2-Dimethyl-I S-methylcarbamoyl-propyl)-3R-(3-pyridin-4-yl pyrrol- I -yl)-succinamic acid; WO 00/04892 PCT/US99/13948 -212 1-((2-Pyridyl)-4-piperazine- 1 -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 1-[ 4 -(Pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperdine-2 carboxylic acid hydroxyamide; 5 N-( 4 -Phenoxy-benzenesulfonyl)-D-tert-leucine; N-( 4 -Phenoxy-benzenesulfonyl)-D-tert-leucine,N-hydroxyamide; N-(8-oxo-4-oxa-1,7-tricyclo[9.6.1.0,12,17]octadeca 11 (18),12(17),13,15-tetraen- 9 -yl)- 3 -[ 4 -(4-pyridyl)-3-phenyl-pyrrol-1-yl) succinamic acid; 10 3-[3-(4-Pyridyl)phenyl-4-yl-pyrrol-1-yl]-N-[2,2-dimethyl-1-(4 pyridyl)carbamoyl-propyl]-succinamic acid; 2 , 2 -Dimethyl-4-[4-(pyridin-2-yloxy)-benzenesulfonyl]-thio morpholine-3-carboxylic acid hydroxyamide; N-[ 4 -( 4 -Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine; 15 N-[ 4 -( 4 -Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; 2 -[2-(N'-Acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl pentanoic acid; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2 20 dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide hydrochloride; 2 -[ 4 -( 4 -Chloro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl butyric acid; 2-[ 4 -( 4 -Chloro-phenoxy)-benzenesulfonylamino)-N-hydroxy-3,3 dimethyl-butyramide; 25 3(R)-N-Hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2 dimethyl-tetrahydro-2H- 1,4-thiazine-3-carboxamide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D cysteine; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D 30 cysteine, N-hydroxyamide; 2 -[ 4 -(Pyridin-2-yl-oxy)-benzenesulfonylamino]-3,3-dimethyl butyric acid; WO 00/04892 PCTIUS99/13948 -213 2-[4-(Pyridin-2-yl-oxy)-benzenesulfonylamino]-N-hydroxy-3,3 dimethyl butyramide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D cysteine; 5 3-[3-(4'-Carbamoyl-biphenyl-4-yl)-pyrrol-I -yl]-N-(2,2-dimethyl- 1 methylcarbamoyl-propyl)-succinamic acid; 3-[3-(4'-Cyano-biphenyl-4-yl)-pyrrol-1-y]-N-(2,2-dimethyl-1 methylcarbamoyl-propyl)-succinamic acid; 2 -(2-Biphenyl-4-yl-ethylsulfonyl)-cyclohex-1 -ene-carboxylic acid 10 hydroxyamide; 6-(2-Biphenyl-4-yl-ethyl sufonyl)-cyclohex-1-ene-carboxylic acid hydroxyamide; N-(4-Pyridin-4-yl-oxy-benzenesulfonyl)-3,3-dimethyl-S (benzylthio)-D-cysteine; 15 3-[3-4'-Carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-[2,2-dimethyl-1 (pyridin-4-yl-carbamoyl)-propyl]-succinamic acid; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D cysteine, N-hydroxyamide; 1-(4-Phenoxy-piperdine- I -sulfonyl)-piperdine-2-carboxylic acid 20 hydroxyamide; 3(R)-4-[4-(4-Bromo)phenoxybenzenesulfonyl]-2,2-dimethyl tetrahydro-2H-1,4-thiazine-3-carboxylic acid; N-(4-[4-Chloro-phenoxy]-benzenesulfonyl)-3,3-dimethyl-S (methylthio)-D-cysteine; 25 N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S (methylthio)-D-cysteine, N-hydroxyamide; N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S (methylsulfoxy)-D-cysteine, N-hydroxyamide; 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3 30 (pyridin-2-ylsulfanyl)-butyric acid; 2 (R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3 (pyridin-3-ylsulfanyl)-butyric acid; WO 00/04892 PCT/US99/13948 -214 2 (R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3 (pyridin-4-ylsulfanyl)-butyric acid; cis- 2 -( 2 -Phenyl-ethanesulfonyl)-cycloheaxanecarboxylic acid hydroxyamide; 5 3(R)-N-Hydroxy-4-(4-(imidaz- I -yl)phenoxybenzenesulfonyl)-2,2 dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2 dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 4 -[ 2 -( 2 -Hydroxycabamoylmethyl-5-phenyl-pentanoylamino)-4 10 methyl-pentanoyl-benzoic acid methyl ester; trans- 2 -(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxyamide; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid; 2-[4-(4-Chlorophenyl)-piperazine- 1 -sulfonylamino]-3-methyl-3 15 (pyridin-2-ylmethylsulfanyl)-butyric acid; 3R-[3-(4'-Cyano-biphenyl-4-yl)pyrrol-1-yl]-N-[2,2-dimethyl-IS (pyridin-4-ylcarbamoyl)-propyl]-succinamic acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid, N-hydroxyamide; 20 N-(2,2-dimethyl- I -methylcarbamoyl-propyl)-3-[1-(4 fluorophenyl)-1H-pyrrol-3-yl]-succinamic acid; 2(R)-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3 (pyridi-n-2-ylsulfanyl)-butyric acid; 2 -( 2 -Biphenyl- 4 -yl-ethanesulfonyl)-cyclohexanecarboxylic acid 25 hydroxamate; 2-[4-(4-Chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3 (pyridin-2ylmethylsulfanyl)-butyric acid, N-hydroxyamide; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid, 30 N-hydroxyamide; 3-tert-Butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro phenoxy)benzenesulfonylamino)-3-methyl-butyric acid; WO 00/04892 PCT/US99/13948 -215 1-(4-Phenylsulfanyl-piperidine- I -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 1-[ 4 -( 4 -Fluoro-phenoxy)-benzenesulfonyl]-3,3-dimethyl-5-oxo piperazine-2-carboxylic acid; 5 N-(4-[4-Fluorophenoxy]-benzenesulfonylamino)-3-methyl-3-(1 benzyl-imidazole-2-yl-sulfanyl)-butyric acid; 2(R)-[4-(4-Fluoro-phenoxy)benzenesulfonylamino]-3-methyl-3 (pyridi-n-2-yl sulfanyl)-butyric acid, hydroxyamide; 3(R)-N-Hydroxy-4-(4-((pyridin-4-yl)methyl)oxybenzenesulfonyl) 10 2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 1-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-4-(1-methyl-iH imidazole-4-sulfonyl)-piperazine-2-carboxylic acid hydroxamide; N-(2,2-Dimethyl-1 S-methylcarbamoyl-propyl)-3R-[1-(4' cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-succinamic acid; 15 3-Carboxymethylsulfanyl-2-(4-(4-fluoro-phenoxy) benzenesulfonylamino)-3-methyl-butyric acid; 2,2-Dimethyl- 1 -oxo-4-[4-(pyridin-4yloxy)-benzenesulfonyl]- IS 14 thiomorpholine-3-carboxylic acid hydroamide; 1-[4-(Pyridin-2-ylsulfanyl)-piperidine- I -sulfonyl]-piperidine-2 20 carboxylic acid hydroxyamide; 2(R)-[4-(4-(fur-3-yl)-phenoxy)-benzenesulfonylamino]-3-methyl 3-(pyridi-n-yl-sulfanyl)-butyric acid; 2,2-Dimethyl-1-oxo-4-[ 4 -(pyridin-4yloxy)-benzenesulfonyl]-1S14 thiomorpholine-3-carboxylic acid hydroamide; 25 {2-[ 4 -(4-Fluoro-phenoxy)-benzenesulfonylamino]-2 hydroxycarbamoyl- 1,1 -dimethyl-ethylsulfanyl} -acetic acid tert-butyl ester; 1-[4-(Pyridin-4-ylsulfanyl)-piperidine- 1 -sulfonyl]-piperidine-2 carboxylic acid hydroxyamide; 2 (R)-[ 4 -( 4 -Bromo-phenoxy)benzenesulfonylamino]-3-methyl-3 30 (pyridi-n-yl-sulfanyl)-butyric acid, hydroxyamide; trans- 2 -( 2 -Biphenyl- 4 -yl-ethylsulfanyl)-cyclohexanecarboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -216 N- [1 S-(1H-Imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-yl phenyl)-pyrrol- I -yl]-succinamic acid formate; N-Methyl-3-[3-(4-pyridin-4-yl-phenyl)-pyrrol-1 -yl]-succinamic acid; 5 N(4)-(2,2-Dimethyl- 1 S-hydroxymethyl-propyl)-N(1)-hydroxy-3R [3-(4-pyridin-4-yl-phenyl)-pyrrol- 1 -yl]-succindiamide; {2-[ 4 -(4-Fluoro-phenoxy)-benzenesulfonylamino]-2 hydroxycarbamoyl- 1,1 -dimethyl-ethylsulfanyl} -acetic acid; 1-[ 4 [( 4 -Fluoro-phenoxy)-benzenesulfonyl)]-3,3-dimethyl-5-oxo 10 piperazine-2-carboxylic acid hydroxyamide; N-(4-[4-Bromophenoxy]-benzenesulfonylamino)-3-methyl-3-( 1 benzyl-imidazole-2-yl-sulfanyl)-butyric acid; 3R-[3-(4'-Cyanobiphenyl-4-yl)-pyrrol-1-yl]-N-(2,2-dimethyl-iS hydroxymethyl-propyl)-succinamic acid; 15 2 -(R)-[4-(4-Iodophenoxy)benzenesulfonylamino]-3-methyl-3 (pyridi-n-2-yl-sulfanyl)-butyric acid; 3R-[3-(4-Cyano-phenyl)-pyrrol- 1 -yl]-N-(2,2-dimethyl- 1S hydroxymethyl-propyl)-succinamic acid; 2(R)-[4-(4-Iodo-phenoxy)benzenesulfonylamino]-3-methyl-3 20 (pyridi-n-yl-sulfonyl)butyric acid, hydroxyamide; 2(R)-[ 4 -( 4 -Nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3 (pyridi-n-yl-sulfonyl)butyric acid; 2-[4-(-Fluoro-phenoxy)-benzene sulfonylamino]-3,3-dimethyl pent-4-enoic acid; 25 2 -[ 4 -( 4 -Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5 methyl-isoxazole-3-ylmethylsulfanyl)-butyric acid; 2 -[ 4 -(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5 methyl-isoazole-3-ylmethylsulfanyl)-butyric acid; 2 -[ 4 -( 4 -Fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3 30 methyl-3-(5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; WO 00/04892 PCT/US99/13948 -217 2-[ 4 -( 4 -Bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3 methyl-3-(5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; 2-[ 4 -( 4 -Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3 (carbomethoxyethylsulfanyl)-butyric acid; 5 1-[ 2 -(Benzothiazol-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine 2-carboxylic acid hydroxyamide; 3R-[3-(4-Cyano-phenyl)-pyrrol-1-yl]-N-(2,2-dimethyl-1 S methylcarbamoyl-propyl)-succinamic acid; 2-[ 4 -( 4 -Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3 10 (hydroxyethylsulfanyl)-butyric acid; [ 4 -Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl sulfanyl)-butyric acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[1 -(4' cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-succinamic acid; 15 2 -[ 4 -(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3 (amidoethylsulfanyl)-butyric acid; [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2 ylsulfanyl)-butyric acid; 2-[ 4 -( 4 -Fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5 20 phenyl-pent-4-enoic acid; 5-[ 4 -( 4 -Fluoro-phenoxy)-benzenesulfonyl]-4,5,6,7-tetrahydro-3H imidazole[4,5,-c]pyridine-6-carboxylic acid hydroxyamide 2(R)-[ 4 -( 4 -Methylphenoxy)benzenesulfonylamino]-3-methyl-3 (pyridi-n-yl-sulfonyl)butyric acid; 25 3 (S)- 4 -( 4 -((Pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl tetrahydro-2H-1,4-thiazine-3-carboxylic acid; 1-[4-(Pyridin-4-ylsulfanyl)-piperidine- I -sulfanyl]-piperidine-2 carboxylic acid hydroxyamide; N- [1 -(1 H-imidazol-2-yl)-3-methyl-butyl]-3-[1-(4'-cyanobiphenyl 30 4-yl)-1H-pyrrol-3-yl]-succinamic acid; 3R-{3-[( 4 -Cyano-phenyl)-acetyl]-pyrrol-l-yl}-N-(2,2-dimethyl 1 S-methylcarbamoyl-propyl)-succinamic acid; WO 00/04892 PCTIUS99/13948 -218 1-[4-(4-Methoxy-phenylsulfamyl)-piperidine- 1 -sulfonyl] piperidine-2-carboxylic acid hydroxamide; 3R-[3-(4-Cyano-phenyl)-pyrrol- 1-yl]-N-(2,2-dimethyl- I S methylcarbamoyl-propyl)-succinamic acid methyl ester; 5 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3 (pyridi-n-yl-sulfonyl)butyric acid, hydroxyamide; 1-[ 4 -(4-Methyl-phenylsulfamyl)-piperidine- 1 -sulfonyl]-piperidine 2-carboxylic acid hydroxamide; 4 -( 4 -Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3 10 carboxylic acid; 4 - 4 (-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3 carboxylic acid hydroxyamide; 4-[ 4 -(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl thiomorpholine-3-carboxylic acid; 15 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl thiomorpholine-3-carboxylic acid hydroxyamide; 2(R)-[4-(4-bromo-phenoxy)benzenesulfoxylamino]-3-methyl-3 (pyridi-n-yl-sulfuroxide)butyric acid, hydroxyamide; 4-(4-Methoxy-bezensulfonyl)-2,2-dimethyl- I -oxo-thiomorpholine 20 3-carboxylic acid hydroxyamide; 2,2-Dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyl] thiomorpholin-3-ol; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethoxy-1-oxo thiomorpholine-3-carboxylic acid hydroxyamide; 25 2-(R)-3-Methyl-3-(pyridin-2-yl-sulfanyl)-[4-(4 trifluoromethylphenoxy)benzenesulfonylamino]-butyric acid; 3(R)-4-(4-(Pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl tetrahydro-2H- 1,4-thiazine-3-carboxamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4 30 (pyridin-4-yl-oxy)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3 yl)methylsulfanyl]-[ 4 -(pyridin-4-yl-oxy)-benzenesulfonylamino] butyramide; WO 00/04892 PCT/US99/13948 -219 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-3-hydroxy-3 methyl-butyric acid; 3(S)-2,2-Dimethyl-4-[ 4 -(pyridin-4-ylsulfanyl)-benzenesulfonyl] thiomorpholine-3-carboxylic acid hydroxyamide; 5 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4 (pyridin-4-yl-sulfanyl)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3 yl)methylsulfanyl]-[ 4 -(pyridin-4-yl-sulfanyl)-benzenesulfonylamino] butyramide; 10 3,3-Dimethyl-2R-[ 4 -(pyridin-4-ylsulfanyl)-piperidine-1 sulfonylamino]-butyric acid; 3,3-Dimethyl-N-hydroxy-2R-[ 4 -(pyridin-4-ylsulfanyl)-piperidine I -sulfonylamino]-butyramide; 2R-[ 4 -( 4 -Bromophenoxy)-benzenesulfonylamino]-N-hydroxy-3 15 methyl-3-[(1 -methyl-imidazol-2-yl)methylsulfanyl]-butyramide; 2 R-[ 4 -(4-Bromophenoxy)-benzenesulfonylamino]-3-methyl-3-[( 1 methyl-imidazol-2-yl)methylsulfanyl]-butyric acid; N-Hydroxy-2-[(4-methylbenzenesulfonyl)amino]acetamide; 1-[4-(4-Imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine 20 2-carboxylic acid hydroxyamide; 1-[4-(4-Imidazol-1-yl-phenylsulfanyl)-piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxyamide; 2 (R)-[ 4 -( 4 -Chloro-benzoyl)-cyclohexanesulfonyl]-piperidine-1 carboxylic acid hydroxyamide; 25 1(R)-[4-(4-Chloro-benzoyl)-piperidine-1-sulfonyl]-piperidine-2 carboxylic acid amide; 1 (R)-(4-Pyridin-2-yl-piperazine- I -sulfonyl)-piperidine-2 carboxylic acid hydroxyamide; I (R)-[4-(4-Imidazol- I -yl-phenoxy)-piperidine- 1 -sulfonyl] 30 piperidine-2-carboxylic acid; 1(R)-[4-(4-Imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl] piperidine-2-carboxylic acid hydroxyamide; WO 00/04892 PCT/US99/13948 -220 N-Hydroxy-3,3-dimethyl-2R-[4-(morpholine-4 carbonyl)piperidine- 1 -sulfonylamino]butyramide; N-Hydroxy-3-methyl-3-(5-methyl-isoxazol-3-yl-methylsulfanyl) 2R-[ 4 -(pyridin-4-ylsulfanyl)-piperidine-sulfonylamino]-butyramide; 5 4-(4'-Chloro-biphenyl-4-yl)-2RS-[2-(1,3-dioxo- 1,3-dihydro isoindol-2-yl)-ethyl]-4-oxo-butyric acid; 4-(4'-Chloro-biphenyl-4-yl)-2R-[2-(1,3-dioxo-1,3-dihydro isoindol-2-yl)-ethyl]-4-oxo-butyric acid; N-Hydroxy-2R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1 10 sulfonylamino]-3,3-dimethyl-butyramide; 2 R-[4-(4-Chloro-benzoyl)-piperazine-1-sulfonylamino]-N hydroxy-3-methyl-3-methylsulfanyl-butyramide; N-Hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4 ylsulfanyl)-piperidine-1-sulfonylamino]-butyramide; 15 4-(Pyridin-4-yloxy)benzenesulfonic acid; 4-(Pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride; (3S)-2,2-Dimethyl-3-thiomorpholine carboxylic acid; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2 dimethyl-1,1-dioxo-tetrahydro-2H-1,4-thiazine-3-carboxamide; 20 1R-3S-2,2-Dimethyl-1-oxo-4-[4-(pyridin-4-yloxy) benzenesulfonyl]-1-thiomorpholine-3-carboxylic acid amide; IS-3S-2,2-Dimethyl-1-oxo-4-[4-(pyridin-4-yloxy) benzenesulfonyl]-1-thiomorpholine-3-carboxylic acid amide; and 4-[4-(1 -Hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl 25 thiomorpholine-3-carboxylic acid amide.