EP1463715A1 - Nouveaux antagonistes de glucagon - Google Patents
Nouveaux antagonistes de glucagonInfo
- Publication number
- EP1463715A1 EP1463715A1 EP02804158A EP02804158A EP1463715A1 EP 1463715 A1 EP1463715 A1 EP 1463715A1 EP 02804158 A EP02804158 A EP 02804158A EP 02804158 A EP02804158 A EP 02804158A EP 1463715 A1 EP1463715 A1 EP 1463715A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- compound according
- hydrogen
- aryl
- ocf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229960004666 glucagon Drugs 0.000 title claims abstract description 66
- 108060003199 Glucagon Proteins 0.000 title claims abstract description 63
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 title claims abstract description 63
- 102000051325 Glucagon Human genes 0.000 title claims abstract description 62
- 239000005557 antagonist Substances 0.000 title abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- 238000000034 method Methods 0.000 claims description 408
- 239000000203 mixture Substances 0.000 claims description 121
- 229910052739 hydrogen Inorganic materials 0.000 claims description 108
- 239000001257 hydrogen Substances 0.000 claims description 80
- -1 C^-alkanoyl Chemical group 0.000 claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims description 55
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 54
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 51
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 50
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 150000002367 halogens Chemical group 0.000 claims description 48
- 238000002360 preparation method Methods 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 41
- 150000002431 hydrogen Chemical group 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 28
- 229960005419 nitrogen Drugs 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 108090001061 Insulin Proteins 0.000 claims description 23
- 102000004877 Insulin Human genes 0.000 claims description 23
- 229940125396 insulin Drugs 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 19
- 229910052717 sulfur Chemical group 0.000 claims description 19
- 239000011593 sulfur Chemical group 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 238000000159 protein binding assay Methods 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 239000008103 glucose Substances 0.000 claims description 9
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 8
- 239000000883 anti-obesity agent Substances 0.000 claims description 8
- 229940125710 antiobesity agent Drugs 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003524 antilipemic agent Substances 0.000 claims description 6
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 201000001421 hyperglycemia Diseases 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 230000003042 antagnostic effect Effects 0.000 claims description 5
- 239000003472 antidiabetic agent Substances 0.000 claims description 5
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 230000009286 beneficial effect Effects 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 4
- 229940030600 antihypertensive agent Drugs 0.000 claims description 4
- 239000002220 antihypertensive agent Substances 0.000 claims description 4
- 125000000732 arylene group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 229940125708 antidiabetic agent Drugs 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000000556 agonist Substances 0.000 abstract description 16
- 230000009471 action Effects 0.000 abstract description 7
- 108010063919 Glucagon Receptors Proteins 0.000 abstract description 5
- 102100040890 Glucagon receptor Human genes 0.000 abstract description 5
- 239000000813 peptide hormone Substances 0.000 abstract description 5
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 173
- 238000005160 1H NMR spectroscopy Methods 0.000 description 146
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 90
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 239000002253 acid Substances 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 35
- 235000019260 propionic acid Nutrition 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 29
- 229920005989 resin Polymers 0.000 description 29
- 239000011347 resin Substances 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 19
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000000872 buffer Substances 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 239000002244 precipitate Substances 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 229940093499 ethyl acetate Drugs 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000004026 insulin derivative Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 13
- 229960003105 metformin Drugs 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000012528 membrane Substances 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 239000011324 bead Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 229940086542 triethylamine Drugs 0.000 description 10
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 9
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 9
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 9
- 239000007995 HEPES buffer Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229950004994 meglitinide Drugs 0.000 description 9
- 229960002354 repaglinide Drugs 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000011539 homogenization buffer Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- GDNOYVMHHMSZJV-UHFFFAOYSA-M 2-(3,4-dimethyl-1,3-thiazol-3-ium-5-yl)ethanol;iodide Chemical compound [I-].CC1=C(CCO)SC=[N+]1C GDNOYVMHHMSZJV-UHFFFAOYSA-M 0.000 description 7
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 7
- 239000008188 pellet Substances 0.000 description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 7
- 108010001478 Bacitracin Proteins 0.000 description 6
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 6
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 6
- 229940122355 Insulin sensitizer Drugs 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 229940100389 Sulfonylurea Drugs 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229960003071 bacitracin Drugs 0.000 description 6
- 229930184125 bacitracin Natural products 0.000 description 6
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 6
- 125000002837 carbocyclic group Chemical group 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229960004580 glibenclamide Drugs 0.000 description 6
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004452 microanalysis Methods 0.000 description 6
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 6
- 239000000700 radioactive tracer Substances 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 description 5
- 108091006905 Human Serum Albumin Proteins 0.000 description 5
- 102000008100 Human Serum Albumin Human genes 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 5
- 229960001641 troglitazone Drugs 0.000 description 5
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 208000002705 Glucose Intolerance Diseases 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 201000009104 prediabetes syndrome Diseases 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
- PNFPBTGYXQEHLP-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)=CC(=O)C1=CC=C(OC(F)(F)F)C=C1 PNFPBTGYXQEHLP-UHFFFAOYSA-N 0.000 description 3
- FMZRKVPGBNTOLY-UHFFFAOYSA-N 3-[[4-[4-[3,5-bis(trifluoromethyl)phenyl]-2-(4-cyclohexylphenyl)-4-oxobutanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 FMZRKVPGBNTOLY-UHFFFAOYSA-N 0.000 description 3
- KUHNCPCUPOPMDY-UHFFFAOYSA-N 4-cyclohexylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1CCCCC1 KUHNCPCUPOPMDY-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- 102100021752 Corticoliberin Human genes 0.000 description 3
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 3
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
- 101000886868 Homo sapiens Gastric inhibitory polypeptide Proteins 0.000 description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 3
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 3
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000034527 Retinoid X Receptors Human genes 0.000 description 3
- 108010038912 Retinoid X Receptors Proteins 0.000 description 3
- 229960002632 acarbose Drugs 0.000 description 3
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002825 functional assay Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 102000050325 human granulocyte inhibitory Human genes 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960004592 isopropanol Drugs 0.000 description 3
- 210000003292 kidney cell Anatomy 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 3
- 229960004844 lovastatin Drugs 0.000 description 3
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- GYBHAJPZBZVOMM-UHFFFAOYSA-N methyl 3-[(4-formylbenzoyl)amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC=C(C=O)C=C1 GYBHAJPZBZVOMM-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 3
- 229960000698 nateglinide Drugs 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229960005095 pioglitazone Drugs 0.000 description 3
- 229920005990 polystyrene resin Polymers 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- WMUIIGVAWPWQAW-XMMPIXPASA-N (2r)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid Chemical compound C1=CC(C[C@@H](OCC)C(O)=O)=CC=C1OCCN1C2=CC=CC=C2OC2=CC=CC=C21 WMUIIGVAWPWQAW-XMMPIXPASA-N 0.000 description 2
- FFEKJBVVAJTQST-WLHGVMLRSA-N (e)-but-2-enedioic acid;1,1-dimethyl-2-(2-morpholin-4-ylphenyl)guanidine Chemical compound OC(=O)\C=C\C(O)=O.CN(C)C(N)=NC1=CC=CC=C1N1CCOCC1 FFEKJBVVAJTQST-WLHGVMLRSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- NUUYRPFSWSHDGG-UHFFFAOYSA-N 1-[4-(1,3-dioxolan-2-yl)phenyl]cyclohexan-1-ol Chemical compound C=1C=C(C2OCCO2)C=CC=1C1(O)CCCCC1 NUUYRPFSWSHDGG-UHFFFAOYSA-N 0.000 description 2
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- YNGGRNROMJXLCP-UHFFFAOYSA-N 2,3-dihydro-1h-indene-5-carbaldehyde Chemical compound O=CC1=CC=C2CCCC2=C1 YNGGRNROMJXLCP-UHFFFAOYSA-N 0.000 description 2
- IWSVLBKHBJGMAA-UHFFFAOYSA-M 2-(3-benzyl-4-methyl-1,3-thiazol-3-ium-5-yl)ethanol;chloride Chemical compound [Cl-].CC1=C(CCO)SC=[N+]1CC1=CC=CC=C1 IWSVLBKHBJGMAA-UHFFFAOYSA-M 0.000 description 2
- BDQRQMLWZJQQKS-UHFFFAOYSA-M 2-(3-ethyl-4-methyl-1,3-thiazol-3-ium-5-yl)ethanol;bromide Chemical compound [Br-].CC[N+]1=CSC(CCO)=C1C BDQRQMLWZJQQKS-UHFFFAOYSA-M 0.000 description 2
- ZYIMHOWVWWHLDN-UHFFFAOYSA-N 2-(4-bromophenyl)-1,3-dioxolane Chemical compound C1=CC(Br)=CC=C1C1OCCO1 ZYIMHOWVWWHLDN-UHFFFAOYSA-N 0.000 description 2
- RFLPSJPHZFUCHR-UHFFFAOYSA-N 2-(4-cyclohexylphenyl)-3-(4-methoxycarbonylphenyl)propanoic acid Chemical compound C1=CC(C(=O)OC)=CC=C1CC(C(O)=O)C1=CC=C(C2CCCCC2)C=C1 RFLPSJPHZFUCHR-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- XGJJEWLCWUYGMD-USHMODERSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-(3,5-dichlorophenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC(Cl)=CC(Cl)=C1 XGJJEWLCWUYGMD-USHMODERSA-N 0.000 description 2
- XVFOPHRGMLWZOJ-JCMHNJIXSA-N 3-[[4-[(z)-4-oxo-2,4-bis[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC(F)(F)F)=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 XVFOPHRGMLWZOJ-JCMHNJIXSA-N 0.000 description 2
- ZVFIKUIDKMTPGN-RRAHZORUSA-N 3-[[4-[(z)-4-oxo-2-(4-phenylphenyl)-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C=1C=CC=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 ZVFIKUIDKMTPGN-RRAHZORUSA-N 0.000 description 2
- DPLJNTWBXCKJOL-UHFFFAOYSA-N 3-bromo-4,5-diethoxybenzonitrile Chemical compound CCOC1=CC(C#N)=CC(Br)=C1OCC DPLJNTWBXCKJOL-UHFFFAOYSA-N 0.000 description 2
- ZROINSWMCSEKMA-UHFFFAOYSA-N 4-(cyclohexen-1-yl)benzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CCCCC1 ZROINSWMCSEKMA-UHFFFAOYSA-N 0.000 description 2
- OTDRMAHWPCGVBL-UHFFFAOYSA-N 4-[2-(4-cyclohexylphenyl)-3-oxo-3-[4-(trifluoromethoxy)anilino]propyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CC(C=1C=CC(=CC=1)C1CCCCC1)C(=O)NC1=CC=C(OC(F)(F)F)C=C1 OTDRMAHWPCGVBL-UHFFFAOYSA-N 0.000 description 2
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 2
- WRDABNWSWOHGMS-UHFFFAOYSA-N AEBSF hydrochloride Chemical compound Cl.NCCC1=CC=C(S(F)(=O)=O)C=C1 WRDABNWSWOHGMS-UHFFFAOYSA-N 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 2
- 101800001982 Cholecystokinin Proteins 0.000 description 2
- 102100025841 Cholecystokinin Human genes 0.000 description 2
- 102100032165 Corticotropin-releasing factor-binding protein Human genes 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- 102000001267 GSK3 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 102000030595 Glucokinase Human genes 0.000 description 2
- 108010021582 Glucokinase Proteins 0.000 description 2
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010057186 Insulin Glargine Proteins 0.000 description 2
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000000637 Melanocyte-Stimulating Hormone Substances 0.000 description 2
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 2
- 101710151321 Melanostatin Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102100040200 Mitochondrial uncoupling protein 2 Human genes 0.000 description 2
- 102400000064 Neuropeptide Y Human genes 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- 229940123464 Thiazolidinedione Drugs 0.000 description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229960001761 chlorpropamide Drugs 0.000 description 2
- 229940107137 cholecystokinin Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 108010083720 corticotropin releasing factor-binding protein Proteins 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- GRTGGSXWHGKRSB-UHFFFAOYSA-N dichloromethyl methyl ether Chemical compound COC(Cl)Cl GRTGGSXWHGKRSB-UHFFFAOYSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000000105 evaporative light scattering detection Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960001381 glipizide Drugs 0.000 description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000003345 hyperglycaemic effect Effects 0.000 description 2
- 229940126904 hypoglycaemic agent Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 229940060975 lantus Drugs 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940035736 metformin and pioglitazone Drugs 0.000 description 2
- VHMGYHFYSWICSP-AENDTGMFSA-N methyl (2r)-3-amino-2-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](O)CN VHMGYHFYSWICSP-AENDTGMFSA-N 0.000 description 2
- OLTCHYNIGIIXDD-UHFFFAOYSA-N methyl 3-[[4-[4-[3,5-bis(trifluoromethyl)phenyl]-2-(4-cyclohexylphenyl)-4-oxobutanoyl]benzoyl]amino]propanoate Chemical compound C1=CC(C(=O)NCCC(=O)OC)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 OLTCHYNIGIIXDD-UHFFFAOYSA-N 0.000 description 2
- NRWBOZGFNPHASN-UHFFFAOYSA-N methyl 4-[3-chloro-2-(4-cyclohexylphenyl)-3-oxopropyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CC(C(Cl)=O)C1=CC=C(C2CCCCC2)C=C1 NRWBOZGFNPHASN-UHFFFAOYSA-N 0.000 description 2
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000002683 reaction inhibitor Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 230000000697 serotonin reuptake Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- MQSXZQXHIJMNAF-UHFFFAOYSA-N skyrin Chemical compound O=C1C2=C(O)C=C(C)C=C2C(=O)C2=C1C(O)=CC(O)=C2C1=C(C(=O)C=2C(=C(O)C=C(C=2)C)C2=O)C2=C(O)C=C1O MQSXZQXHIJMNAF-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229960002277 tolazamide Drugs 0.000 description 2
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 2
- 229960005371 tolbutamide Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical group CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- JSCMRWULRQOADA-PWXSHKNQSA-N (2r)-3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-(4-phenylphenyl)butanoyl]benzoyl]amino]-2-hydroxypropanoic acid Chemical compound C1=CC(C(=O)NC[C@@H](O)C(O)=O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 JSCMRWULRQOADA-PWXSHKNQSA-N 0.000 description 1
- FLOKZRNCJPQCJE-BDJZEIKTSA-N (2r)-3-[[4-[4-(4-cyclohexylphenyl)-4-oxo-2-(4-propan-2-ylphenyl)butanoyl]benzoyl]amino]-2-hydroxypropanoic acid Chemical compound C1=CC(C(C)C)=CC=C1C(C(=O)C=1C=CC(=CC=1)C(=O)NC[C@@H](O)C(O)=O)CC(=O)C1=CC=C(C2CCCCC2)C=C1 FLOKZRNCJPQCJE-BDJZEIKTSA-N 0.000 description 1
- OLNJKAXRBXUBTB-JYJNAYRXSA-N (2s)-2-[[(2s)-2-[[(2s)-2-acetamido-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N OLNJKAXRBXUBTB-JYJNAYRXSA-N 0.000 description 1
- QNDFBOXBUCDYNZ-NRFANRHFSA-N (2s)-2-ethoxy-3-[4-[2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]ethoxy]phenyl]propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(NC(=O)OC(C)(C)C)C=C1 QNDFBOXBUCDYNZ-NRFANRHFSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- BGNORAQHPDCDDJ-UHFFFAOYSA-N 1,2,3,4,6,7,8,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1=CCCCN2CCCNC21 BGNORAQHPDCDDJ-UHFFFAOYSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000004529 1,2,3-triazinyl group Chemical group N1=NN=C(C=C1)* 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 1
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical class OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- QTFLUVRZOBQTBW-UHFFFAOYSA-N 1,3-thiazol-3-ium;iodide Chemical compound [I-].C1=CSC=[NH+]1 QTFLUVRZOBQTBW-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- XCSRDHYEONHVMI-UHFFFAOYSA-N 1-(2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)ethanone Chemical compound O1C(F)(F)C(F)(F)OC2=CC(C(=O)C)=CC=C21 XCSRDHYEONHVMI-UHFFFAOYSA-N 0.000 description 1
- JGMBBKVZFUHCJC-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC(Cl)=CC(Cl)=C1 JGMBBKVZFUHCJC-UHFFFAOYSA-N 0.000 description 1
- MCYCSIKSZLARBD-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MCYCSIKSZLARBD-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 150000002397 1-phenylpyrazoles Chemical class 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- RVXSASLSNHDASC-OSWDIKPLSA-N 110084-95-2 Chemical group C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 RVXSASLSNHDASC-OSWDIKPLSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- CJGXJKVMUHXVHL-UHFFFAOYSA-N 2,2-dimethylpropylbenzene Chemical compound CC(C)(C)CC1=CC=CC=C1 CJGXJKVMUHXVHL-UHFFFAOYSA-N 0.000 description 1
- VAZZQRFSDNZKPO-UHFFFAOYSA-N 2,3-dihydro-1h-indene-4-carbaldehyde Chemical compound O=CC1=CC=CC2=C1CCC2 VAZZQRFSDNZKPO-UHFFFAOYSA-N 0.000 description 1
- NVYSVDRYESXWBD-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfanyl)-1-(3,4-dihydroxyphenyl)ethanone Chemical class C1=C(O)C(O)=CC=C1C(=O)CSC1=NC2=CC=CC=C2N1 NVYSVDRYESXWBD-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- LZJXTXRCENENLT-UHFFFAOYSA-N 2-(3,5-dichlorophenyl)propan-2-ol Chemical compound CC(C)(O)C1=CC(Cl)=CC(Cl)=C1 LZJXTXRCENENLT-UHFFFAOYSA-N 0.000 description 1
- QMRTUCUDEYLJNU-UHFFFAOYSA-N 2-(4-cyclohexylphenyl)-3-(4-methoxycarbonylphenyl)prop-2-enoic acid Chemical compound C1=CC(C(=O)OC)=CC=C1C=C(C(O)=O)C1=CC=C(C2CCCCC2)C=C1 QMRTUCUDEYLJNU-UHFFFAOYSA-N 0.000 description 1
- ZHMWKJWMWIWEPJ-UHFFFAOYSA-N 2-(4-cyclohexylphenyl)acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1CCCCC1 ZHMWKJWMWIWEPJ-UHFFFAOYSA-N 0.000 description 1
- FHEYFIGWYQJVDR-ACJLOTCBSA-N 2-[[3-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1h-indol-7-yl]oxy]acetic acid Chemical compound C1([C@@H](O)CN[C@@H](CC=2C3=CC=CC(OCC(O)=O)=C3NC=2)C)=CC=CC(Cl)=C1 FHEYFIGWYQJVDR-ACJLOTCBSA-N 0.000 description 1
- LUACLLSCZRRTIH-UPHRSURJSA-N 2-[[4-[(z)-4-[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-enoxy]phenyl]methyl]-1,2,4-oxadiazolidine-3,5-dione Chemical compound O1C(=O)NC(=O)N1CC(C=C1)=CC=C1OC\C=C/COC(C=C1)=CC=C1CN1C(=O)NC(=O)O1 LUACLLSCZRRTIH-UPHRSURJSA-N 0.000 description 1
- BJBCSGQLZQGGIQ-QGZVFWFLSA-N 2-acetamidoethyl (2r)-2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetate Chemical compound O([C@@H](C(=O)OCCNC(=O)C)C=1C=CC(Cl)=CC=1)C1=CC=CC(C(F)(F)F)=C1 BJBCSGQLZQGGIQ-QGZVFWFLSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- UBCGKDWJYIGQAS-IMRQLAEWSA-N 2-hydroxy-3-[[4-[(z)-4-oxo-2-(4-phenylphenyl)-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCC(O)C(O)=O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C=1C=CC=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 UBCGKDWJYIGQAS-IMRQLAEWSA-N 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- QVMAPISVIMTMBY-UHFFFAOYSA-N 3-[(4-formylbenzoyl)amino]propanoic acid Chemical compound OC(=O)CCNC(=O)C1=CC=C(C=O)C=C1 QVMAPISVIMTMBY-UHFFFAOYSA-N 0.000 description 1
- PNFPBTGYXQEHLP-VFCFBJKWSA-N 3-[[4-[(e)-2-(4-cyclohexylphenyl)-4-oxo-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C\C(=O)C1=CC=C(OC(F)(F)F)C=C1 PNFPBTGYXQEHLP-VFCFBJKWSA-N 0.000 description 1
- KTSLKMRVAAEGEG-NQUVTRGKSA-N 3-[[4-[(z)-2,4-bis(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(C2CCCCC2)C=C1 KTSLKMRVAAEGEG-NQUVTRGKSA-N 0.000 description 1
- ZVDMWZQZSJRIQQ-RRAHZORUSA-N 3-[[4-[(z)-2-(4-chlorophenyl)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(Cl)=CC=1)=C/C(=O)C1=CC=C(C2CCCCC2)C=C1 ZVDMWZQZSJRIQQ-RRAHZORUSA-N 0.000 description 1
- PENQGTXEGNGENY-VAMRJTSQSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-(2,3-dihydro-1h-inden-5-yl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(CCC2)C2=C1 PENQGTXEGNGENY-VAMRJTSQSA-N 0.000 description 1
- FLXKKULJGRLLTR-XHPQRKPJSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-(3,4-difluorophenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(F)C(F)=C1 FLXKKULJGRLLTR-XHPQRKPJSA-N 0.000 description 1
- QMLFFUOTPNEXHX-GIBOGKFOSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-(4-cyclopentylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(C2CCCC2)C=C1 QMLFFUOTPNEXHX-GIBOGKFOSA-N 0.000 description 1
- NMWOMWARVLYXSZ-ANYBSYGZSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-(4-methoxyphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C(C=1C=CC(=CC=1)C1CCCCC1)/C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 NMWOMWARVLYXSZ-ANYBSYGZSA-N 0.000 description 1
- PWDUZZLRGLILPL-ANYBSYGZSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-(4-methylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C)=CC=C1C(=O)\C=C(C=1C=CC(=CC=1)C1CCCCC1)/C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 PWDUZZLRGLILPL-ANYBSYGZSA-N 0.000 description 1
- KVQYYRNBVZZDQI-SJIPCVTESA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-[4-(2-methylpropyl)phenyl]-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(CC(C)C)=CC=C1C(=O)\C=C(C=1C=CC(=CC=1)C1CCCCC1)/C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 KVQYYRNBVZZDQI-SJIPCVTESA-N 0.000 description 1
- JELFGHSRURMFPF-NQUVTRGKSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-(4-phenoxyphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 JELFGHSRURMFPF-NQUVTRGKSA-N 0.000 description 1
- DNBGCKNLLHQCKD-NQUVTRGKSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-(4-phenylphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 DNBGCKNLLHQCKD-NQUVTRGKSA-N 0.000 description 1
- NJWGMLBSPIGIBC-VAMRJTSQSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-(4-propan-2-ylphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(C)C)=CC=C1C(=O)\C=C(C=1C=CC(=CC=1)C1CCCCC1)/C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 NJWGMLBSPIGIBC-VAMRJTSQSA-N 0.000 description 1
- GXHZDTKQUZVTAB-OOAXWGSJSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-[2-(trifluoromethyl)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=CC=C1C(F)(F)F GXHZDTKQUZVTAB-OOAXWGSJSA-N 0.000 description 1
- XCEQRFYDYKGXKA-RRAHZORUSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-[3-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=CC(OC(F)(F)F)=C1 XCEQRFYDYKGXKA-RRAHZORUSA-N 0.000 description 1
- KJGYGTXHKGRBLF-RRAHZORUSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-[4-(trifluoromethylsulfanyl)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(SC(F)(F)F)C=C1 KJGYGTXHKGRBLF-RRAHZORUSA-N 0.000 description 1
- LOEQTAOBFLFCQW-HFTWOUSFSA-N 3-[[4-[(z)-2-(4-cyclohexylphenyl)-4-oxo-4-phenylbut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=CC=C1 LOEQTAOBFLFCQW-HFTWOUSFSA-N 0.000 description 1
- YRKGSZOBYXSMSS-RRAHZORUSA-N 3-[[4-[(z)-2-[4-(cyclohexen-1-yl)phenyl]-4-oxo-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C=1CCCCC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 YRKGSZOBYXSMSS-RRAHZORUSA-N 0.000 description 1
- LBBNIXKEWILGLE-DIBXZPPDSA-N 3-[[4-[(z)-4-(1,3-benzodioxol-5-yl)-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(OCO2)C2=C1 LBBNIXKEWILGLE-DIBXZPPDSA-N 0.000 description 1
- NXRRUVCGKVQPEY-OOAXWGSJSA-N 3-[[4-[(z)-4-(2-chlorophenyl)-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=CC=C1Cl NXRRUVCGKVQPEY-OOAXWGSJSA-N 0.000 description 1
- VLDYFIZUUISEFP-RRAHZORUSA-N 3-[[4-[(z)-4-(4-chlorophenyl)-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC=C(Cl)C=C1 VLDYFIZUUISEFP-RRAHZORUSA-N 0.000 description 1
- BUHIVRBNGDRISI-KQWNVCNZSA-N 3-[[4-[(z)-4-(4-chlorophenyl)-2-(4-methylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C)=CC=C1C(\C(=O)C=1C=CC(=CC=1)C(=O)NCCC(O)=O)=C\C(=O)C1=CC=C(Cl)C=C1 BUHIVRBNGDRISI-KQWNVCNZSA-N 0.000 description 1
- NZUPCAIAFZTAIN-RRAHZORUSA-N 3-[[4-[(z)-4-(4-chlorophenyl)-4-oxo-2-(4-phenylphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C=1C=CC=CC=1)=C/C(=O)C1=CC=C(Cl)C=C1 NZUPCAIAFZTAIN-RRAHZORUSA-N 0.000 description 1
- NWDXDTRGZVVASZ-NQUVTRGKSA-N 3-[[4-[(z)-4-(4-cyclohexylphenyl)-4-oxo-2-(4-phenylphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C=1C=CC=CC=1)=C/C(=O)C1=CC=C(C2CCCCC2)C=C1 NWDXDTRGZVVASZ-NQUVTRGKSA-N 0.000 description 1
- HYAKRYXNJRQRDV-VAMRJTSQSA-N 3-[[4-[(z)-4-(4-cyclohexylphenyl)-4-oxo-2-(4-propan-2-ylphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(C)C)=CC=C1C(\C(=O)C=1C=CC(=CC=1)C(=O)NCCC(O)=O)=C\C(=O)C1=CC=C(C2CCCCC2)C=C1 HYAKRYXNJRQRDV-VAMRJTSQSA-N 0.000 description 1
- JBYBUKOVLVXRDJ-DIBXZPPDSA-N 3-[[4-[(z)-4-(4-cyclopentylphenyl)-4-oxo-2-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC(F)(F)F)=CC=1)=C/C(=O)C1=CC=C(C2CCCC2)C=C1 JBYBUKOVLVXRDJ-DIBXZPPDSA-N 0.000 description 1
- GANVBODOQALTAJ-KQWNVCNZSA-N 3-[[4-[(z)-4-(4-methoxyphenyl)-4-oxo-2-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C(C=1C=CC(OC(F)(F)F)=CC=1)/C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 GANVBODOQALTAJ-KQWNVCNZSA-N 0.000 description 1
- APTYQUZIDBOQJO-SXBRIOAWSA-N 3-[[4-[(z)-4-(4-tert-butylphenyl)-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)\C=C(C=1C=CC(=CC=1)C1CCCCC1)/C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 APTYQUZIDBOQJO-SXBRIOAWSA-N 0.000 description 1
- LDDFLZDUVPLDDS-USHMODERSA-N 3-[[4-[(z)-4-[3,5-bis(trifluoromethyl)phenyl]-2-(4-cyclohexylphenyl)-4-oxobut-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C1CCCCC1)=C/C(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 LDDFLZDUVPLDDS-USHMODERSA-N 0.000 description 1
- UANBVFACQUTJDH-RCCKNPSSSA-N 3-[[4-[(z)-4-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-2-(5-thiophen-2-ylthiophen-2-yl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1SC(=CC=1)C=1SC=CC=1)=C\C(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 UANBVFACQUTJDH-RCCKNPSSSA-N 0.000 description 1
- TXONXOVOFBXOIV-SJIPCVTESA-N 3-[[4-[(z)-4-naphthalen-2-yl-4-oxo-2-(4-phenylphenyl)but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(=CC=1)C=1C=CC=CC=1)=C/C(=O)C1=CC=C(C=CC=C2)C2=C1 TXONXOVOFBXOIV-SJIPCVTESA-N 0.000 description 1
- RCWXWMJWUNKPEO-RRAHZORUSA-N 3-[[4-[(z)-4-oxo-2-(3-phenoxyphenyl)-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=C(OC=2C=CC=CC=2)C=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 RCWXWMJWUNKPEO-RRAHZORUSA-N 0.000 description 1
- OLWMDXNMNCZYCG-RRAHZORUSA-N 3-[[4-[(z)-4-oxo-2-(4-phenoxyphenyl)-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC=2C=CC=CC=2)=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 OLWMDXNMNCZYCG-RRAHZORUSA-N 0.000 description 1
- WUEDWMNFRQDXBL-BRPDVVIDSA-N 3-[[4-[(z)-4-oxo-2-(4-phenylmethoxyphenyl)-4-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OCC=2C=CC=CC=2)=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)F)C=C1 WUEDWMNFRQDXBL-BRPDVVIDSA-N 0.000 description 1
- LVFLVEUHAMVFMO-JCMHNJIXSA-N 3-[[4-[(z)-4-oxo-2-[4-(trifluoromethoxy)phenyl]-4-[4-(trifluoromethylsulfanyl)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC(F)(F)F)=CC=1)=C/C(=O)C1=CC=C(SC(F)(F)F)C=C1 LVFLVEUHAMVFMO-JCMHNJIXSA-N 0.000 description 1
- XFUZJRCUNCTGTD-ZHZULCJRSA-N 3-[[4-[(z)-4-oxo-4-(2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)-2-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC(F)(F)F)=CC=1)=C/C(=O)C1=CC=C(OC(F)(F)C(F)(F)O2)C2=C1 XFUZJRCUNCTGTD-ZHZULCJRSA-N 0.000 description 1
- UJMRDYSBOYVGON-ITYLOYPMSA-N 3-[[4-[(z)-4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC(F)(F)F)=CC=1)=C/C(=O)C1=CC=C(CCCC2)C2=C1 UJMRDYSBOYVGON-ITYLOYPMSA-N 0.000 description 1
- VDSJMIVACJSVOF-JWGURIENSA-N 3-[[4-[(z)-4-oxo-4-phenyl-2-[4-(trifluoromethoxy)phenyl]but-2-enoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(\C=1C=CC(OC(F)(F)F)=CC=1)=C/C(=O)C1=CC=CC=C1 VDSJMIVACJSVOF-JWGURIENSA-N 0.000 description 1
- NMLHIGMXCATKPO-UHFFFAOYSA-N 3-[[4-[2-(4-bromothiophen-2-yl)-4-(4-chloro-3-methylphenyl)-4-oxobutanoyl]benzoyl]amino]propanoic acid Chemical compound C1=C(Cl)C(C)=CC(C(=O)CC(C(=O)C=2C=CC(=CC=2)C(=O)NCCC(O)=O)C=2SC=C(Br)C=2)=C1 NMLHIGMXCATKPO-UHFFFAOYSA-N 0.000 description 1
- ABVZODCJZLRFBQ-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-(4-phenoxyphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 ABVZODCJZLRFBQ-UHFFFAOYSA-N 0.000 description 1
- IKHOVYAMCKQFCJ-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-(4-phenylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 IKHOVYAMCKQFCJ-UHFFFAOYSA-N 0.000 description 1
- GBUIXWHFWZAPFH-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-(4-piperidin-1-ylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(N2CCCCC2)C=C1 GBUIXWHFWZAPFH-UHFFFAOYSA-N 0.000 description 1
- SXSPVTMXNYMRJI-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-[2-(trifluoromethyl)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=CC=C1C(F)(F)F SXSPVTMXNYMRJI-UHFFFAOYSA-N 0.000 description 1
- PPFQULWLIKBURR-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(OC(F)(F)F)C=C1 PPFQULWLIKBURR-UHFFFAOYSA-N 0.000 description 1
- ZELQECMSRYWZEG-UHFFFAOYSA-N 3-[[4-[2-(4-cyclohexylphenyl)-4-oxo-4-[4-(trifluoromethylsulfanyl)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(SC(F)(F)F)C=C1 ZELQECMSRYWZEG-UHFFFAOYSA-N 0.000 description 1
- DVMOPLMBPLTHDJ-UHFFFAOYSA-N 3-[[4-[4-(1,3-benzodioxol-5-yl)-2-(4-cyclohexylphenyl)-4-oxobutanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(OCO2)C2=C1 DVMOPLMBPLTHDJ-UHFFFAOYSA-N 0.000 description 1
- MQHFHBQWMFNVSV-UHFFFAOYSA-N 3-[[4-[4-(2-chlorophenyl)-2-(4-cyclohexylphenyl)-4-oxobutanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=CC=C1Cl MQHFHBQWMFNVSV-UHFFFAOYSA-N 0.000 description 1
- RBYDMYDMFGMSMF-UHFFFAOYSA-N 3-[[4-[4-(3-bromophenyl)-4-oxo-2-(4-phenylmethoxyphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(OCC=2C=CC=CC=2)=CC=1)CC(=O)C1=CC=CC(Br)=C1 RBYDMYDMFGMSMF-UHFFFAOYSA-N 0.000 description 1
- CHQSQTQFVNCYKE-UHFFFAOYSA-N 3-[[4-[4-(3-bromophenyl)-4-oxo-2-(4-phenylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C=1C=CC=CC=1)CC(=O)C1=CC=CC(Br)=C1 CHQSQTQFVNCYKE-UHFFFAOYSA-N 0.000 description 1
- LNEXRUYFYAWVBG-UHFFFAOYSA-N 3-[[4-[4-(4-butan-2-ylphenyl)-4-oxo-2-(3-phenoxyphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(C)CC)=CC=C1C(=O)CC(C=1C=C(OC=2C=CC=CC=2)C=CC=1)C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 LNEXRUYFYAWVBG-UHFFFAOYSA-N 0.000 description 1
- XYDKDCWFSLRPTE-UHFFFAOYSA-N 3-[[4-[4-(4-chlorophenyl)-4-oxo-2-(4-phenylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C=1C=CC=CC=1)CC(=O)C1=CC=C(Cl)C=C1 XYDKDCWFSLRPTE-UHFFFAOYSA-N 0.000 description 1
- HIUBNPWVQBJBEQ-UHFFFAOYSA-N 3-[[4-[4-(4-cyclohexylphenyl)-2-(3,5-dichlorophenyl)-4-oxobutanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=C(Cl)C=C(Cl)C=1)CC(=O)C1=CC=C(C2CCCCC2)C=C1 HIUBNPWVQBJBEQ-UHFFFAOYSA-N 0.000 description 1
- DWTMQVSNXIBAMT-UHFFFAOYSA-N 3-[[4-[4-(4-cyclohexylphenyl)-4-oxo-2-(4-propan-2-ylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(C)C)=CC=C1C(C(=O)C=1C=CC(=CC=1)C(=O)NCCC(O)=O)CC(=O)C1=CC=C(C2CCCCC2)C=C1 DWTMQVSNXIBAMT-UHFFFAOYSA-N 0.000 description 1
- FWFFSLFNUBPNNJ-UHFFFAOYSA-N 3-[[4-[4-(4-cyclohexylphenyl)-4-oxo-2-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(OC(F)(F)F)=CC=1)CC(=O)C1=CC=C(C2CCCCC2)C=C1 FWFFSLFNUBPNNJ-UHFFFAOYSA-N 0.000 description 1
- XZGDEXQRRGVWEZ-UHFFFAOYSA-N 3-[[4-[4-(4-tert-butylphenyl)-2-(4-cyclohexylphenyl)-4-oxobutanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CC(C=1C=CC(=CC=1)C1CCCCC1)C(=O)C1=CC=C(C(=O)NCCC(O)=O)C=C1 XZGDEXQRRGVWEZ-UHFFFAOYSA-N 0.000 description 1
- GKFYNXUBVZIQDR-UHFFFAOYSA-N 3-[[4-[4-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-2-(4-phenylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C=1C=CC=CC=1)CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 GKFYNXUBVZIQDR-UHFFFAOYSA-N 0.000 description 1
- GHXMXXFOFDDABW-UHFFFAOYSA-N 3-[[4-[4-naphthalen-2-yl-4-oxo-2-(4-phenylphenyl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C=1C=CC=CC=1)CC(=O)C1=CC=C(C=CC=C2)C2=C1 GHXMXXFOFDDABW-UHFFFAOYSA-N 0.000 description 1
- UHWWQFDFGKFOTJ-UHFFFAOYSA-N 3-[[4-[4-oxo-2-(3-phenoxyphenyl)-4-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=C(OC=2C=CC=CC=2)C=CC=1)CC(=O)C1=CC=C(OC(F)(F)F)C=C1 UHWWQFDFGKFOTJ-UHFFFAOYSA-N 0.000 description 1
- NHDRCXZXWKUBSG-UHFFFAOYSA-N 3-[[4-[4-oxo-2-(4-phenoxyphenyl)-4-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(OC=2C=CC=CC=2)=CC=1)CC(=O)C1=CC=C(OC(F)(F)F)C=C1 NHDRCXZXWKUBSG-UHFFFAOYSA-N 0.000 description 1
- ZJADKPONFUWOGC-UHFFFAOYSA-N 3-[[4-[4-oxo-2-(4-phenylmethoxyphenyl)-4-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(OCC=2C=CC=CC=2)=CC=1)CC(=O)C1=CC=C(OC(F)(F)F)C=C1 ZJADKPONFUWOGC-UHFFFAOYSA-N 0.000 description 1
- GOXBZHAQIVENFH-UHFFFAOYSA-N 3-[[4-[4-oxo-2-(4-phenylphenyl)-4-(2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C=1C=CC=CC=1)CC(=O)C1=CC=C(OC(F)(F)C(F)(F)O2)C2=C1 GOXBZHAQIVENFH-UHFFFAOYSA-N 0.000 description 1
- XOQMWYBGULXTHC-UHFFFAOYSA-N 3-[[4-[4-oxo-2-(4-phenylphenyl)-4-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(=CC=1)C=1C=CC=CC=1)CC(=O)C1=CC=C(OC(F)(F)F)C=C1 XOQMWYBGULXTHC-UHFFFAOYSA-N 0.000 description 1
- BFAGTNWIEXKXJZ-UHFFFAOYSA-N 3-[[4-[4-oxo-4-(4-phenylphenyl)-2-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoic acid Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1C(=O)C(C=1C=CC(OC(F)(F)F)=CC=1)CC(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 BFAGTNWIEXKXJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- CGXKLNLXGJBZBI-UHFFFAOYSA-N 4-(2,2-dimethylpropyl)benzaldehyde Chemical compound CC(C)(C)CC1=CC=C(C=O)C=C1 CGXKLNLXGJBZBI-UHFFFAOYSA-N 0.000 description 1
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 1
- XQNVDQZWOBPLQZ-UHFFFAOYSA-N 4-(trifluoromethoxy)benzaldehyde Chemical compound FC(F)(F)OC1=CC=C(C=O)C=C1 XQNVDQZWOBPLQZ-UHFFFAOYSA-N 0.000 description 1
- LGSOKZOQANLOEU-UHFFFAOYSA-N 4-[2-(2,4-dioxo-1,3-thiazolidin-5-yl)ethoxy]benzonitrile Chemical compound S1C(=O)NC(=O)C1CCOC1=CC=C(C#N)C=C1 LGSOKZOQANLOEU-UHFFFAOYSA-N 0.000 description 1
- OJGLLLGEYJAJGG-UHFFFAOYSA-N 4-[2-[4-(2,2-dimethylpropyl)phenyl]-4-oxo-4-[4-(trifluoromethoxy)phenyl]butanoyl]benzoic acid Chemical compound C1=CC(CC(C)(C)C)=CC=C1C(C(=O)C=1C=CC(=CC=1)C(O)=O)CC(=O)C1=CC=C(OC(F)(F)F)C=C1 OJGLLLGEYJAJGG-UHFFFAOYSA-N 0.000 description 1
- QBQLYIISSRXYKL-UHFFFAOYSA-N 4-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,2-oxazolidine-3,5-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCOC(C=C1)=CC=C1CC1C(=O)NOC1=O QBQLYIISSRXYKL-UHFFFAOYSA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
- NFFXEUUOMTXWCX-UHFFFAOYSA-N 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxy-n-[[4-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound C1=C(C(=O)NCC=2C=CC(=CC=2)C(F)(F)F)C(OC)=CC=C1CC1SC(=O)NC1=O NFFXEUUOMTXWCX-UHFFFAOYSA-N 0.000 description 1
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
- LKKAMJRUPIIUTC-UHFFFAOYSA-N 5-[[4-[(6-methoxy-1-methylbenzimidazol-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione;hydrochloride Chemical compound Cl.CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O LKKAMJRUPIIUTC-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- SLXTWXQUEZSSTJ-UHFFFAOYSA-N 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]pyridine-3-carboxylic acid Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C1(C=2N=CC(=CC=2)C(O)=O)CC1 SLXTWXQUEZSSTJ-UHFFFAOYSA-N 0.000 description 1
- RLYDBONATWKYQX-UHFFFAOYSA-N 6-[4-[2-[[2-hydroxy-3-[(2-oxo-1,3-dihydrobenzimidazol-4-yl)oxy]propyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide Chemical compound C=1C=CC=2NC(=O)NC=2C=1OCC(O)CNC(C)(C)CC(C=C1)=CC=C1OC1=CC=C(C(N)=O)C=N1 RLYDBONATWKYQX-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- RZVHIXYEVGDQDX-UHFFFAOYSA-N 9,10-anthraquinone Chemical group C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 RZVHIXYEVGDQDX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 206010070901 Diabetic dyslipidaemia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- GGUVRMBIEPYOKL-WMVCGJOFSA-N GW 409544 Chemical compound C([C@H](NC(/C)=C\C(=O)C=1C=CC=CC=1)C(O)=O)C(C=C1)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 GGUVRMBIEPYOKL-WMVCGJOFSA-N 0.000 description 1
- 101800002068 Galanin Proteins 0.000 description 1
- 102000019432 Galanin Human genes 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 229940122904 Glucagon receptor antagonist Drugs 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical group N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- 108010008364 Melanocortins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 101710112393 Mitochondrial uncoupling protein 2 Proteins 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000002512 Orexin Human genes 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- DRYDKQOPVBDZMQ-UHFFFAOYSA-N Secalonic acid A Natural products COC(=O)C12Oc3ccc(c(O)c3C(=O)C1=C(O)CC(C)C2O)c4ccc5OC6(C(O)C(C)CC(=C6C(=O)c5c4O)O)C(=O)OC DRYDKQOPVBDZMQ-UHFFFAOYSA-N 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010071769 Thyroid Hormone Receptors beta Proteins 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 108010021111 Uncoupling Protein 2 Proteins 0.000 description 1
- 102000008200 Uncoupling Protein 3 Human genes 0.000 description 1
- 108010021098 Uncoupling Protein 3 Proteins 0.000 description 1
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 1
- 108010059705 Urocortins Proteins 0.000 description 1
- 102000005630 Urocortins Human genes 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 239000003875 Wang resin Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical group C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical class 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003392 amylase inhibitor Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004653 anthracenylene group Chemical group 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 235000021229 appetite regulation Nutrition 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 150000004074 biphenyls Chemical class 0.000 description 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000005566 carbazolylene group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 1
- 229950009226 ciglitazone Drugs 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HHNHBFLGXIUXCM-GFCCVEGCSA-N cyclohexylbenzene Chemical compound [CH]1CCCC[C@@H]1C1=CC=CC=C1 HHNHBFLGXIUXCM-GFCCVEGCSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- QQKNSPHAFATFNQ-UHFFFAOYSA-N darglitazone Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCC(=O)C(C=C1)=CC=C1CC1SC(=O)NC1=O QQKNSPHAFATFNQ-UHFFFAOYSA-N 0.000 description 1
- 229950006689 darglitazone Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 229960001767 dextrothyroxine Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- FUZBPOHHSBDTJQ-CFOQQKEYSA-L disodium;5-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate Chemical compound [Na+].[Na+].C1([C@@H](O)CN[C@@H](CC=2C=C3OC(OC3=CC=2)(C([O-])=O)C([O-])=O)C)=CC=CC(Cl)=C1 FUZBPOHHSBDTJQ-CFOQQKEYSA-L 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229950000269 emiglitate Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 229950002375 englitazone Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- JJOXQBQCJOENPA-SZFCLFMZSA-N ethyl (2r)-3-[[4-[4-(4-tert-butylphenyl)-2-(4-cyclohexylphenyl)-4-oxobutanoyl]benzoyl]amino]-2-hydroxypropanoate Chemical compound C1=CC(C(=O)NC[C@@H](O)C(=O)OCC)=CC=C1C(=O)C(C=1C=CC(=CC=1)C1CCCCC1)CC(=O)C1=CC=C(C(C)(C)C)C=C1 JJOXQBQCJOENPA-SZFCLFMZSA-N 0.000 description 1
- NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2r,3r,4r,5s)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229960001582 fenfluramine Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000005567 fluorenylene group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000018914 glucose metabolism disease Diseases 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000004116 glycogenolysis Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XPGRZDJXVKFLHQ-UHFFFAOYSA-N hydron;methyl 3-aminopropanoate;chloride Chemical compound Cl.COC(=O)CCN XPGRZDJXVKFLHQ-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000002396 hypoinsulinemic effect Effects 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical class II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 239000002865 melanocortin Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- SHUWIDDXCILERF-SNVBAGLBSA-N methyl (2r)-3-[(4-formylbenzoyl)amino]-2-hydroxypropanoate Chemical compound COC(=O)[C@H](O)CNC(=O)C1=CC=C(C=O)C=C1 SHUWIDDXCILERF-SNVBAGLBSA-N 0.000 description 1
- SWPOJNOZJGOYGM-UHFFFAOYSA-N methyl 3-[[4-[4-(4-tert-butylphenyl)-4-oxo-2-[4-(trifluoromethoxy)phenyl]butanoyl]benzoyl]amino]propanoate Chemical compound C1=CC(C(=O)NCCC(=O)OC)=CC=C1C(=O)C(C=1C=CC(OC(F)(F)F)=CC=1)CC(=O)C1=CC=C(C(C)(C)C)C=C1 SWPOJNOZJGOYGM-UHFFFAOYSA-N 0.000 description 1
- IFOPISOXRAHSFE-UHFFFAOYSA-N methyl 4-[4-(4-tert-butylphenyl)-4-oxo-2-[4-(trifluoromethoxy)phenyl]butanoyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C(=O)C(C=1C=CC(OC(F)(F)F)=CC=1)CC(=O)C1=CC=C(C(C)(C)C)C=C1 IFOPISOXRAHSFE-UHFFFAOYSA-N 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- SLZIZIJTGAYEKK-CIJSCKBQSA-N molport-023-220-247 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CNC=N1 SLZIZIJTGAYEKK-CIJSCKBQSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- FJJZLLDDYQTGGH-UHFFFAOYSA-N n'-[6,7-dichloro-3-(2-phenylethenyl)quinoxalin-2-yl]-n,n,n'-trimethylpropane-1,3-diamine Chemical compound CN(C)CCCN(C)C1=NC2=CC(Cl)=C(Cl)C=C2N=C1C=CC1=CC=CC=C1 FJJZLLDDYQTGGH-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 108060005714 orexin Proteins 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- YDCVQGAUCOROHB-UHFFFAOYSA-N oxadiazolidine-4,5-dione Chemical class O=C1NNOC1=O YDCVQGAUCOROHB-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005564 oxazolylene group Chemical group 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000005560 phenanthrenylene group Chemical group 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000018656 positive regulation of gluconeogenesis Effects 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000005550 pyrazinylene group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005576 pyrimidinylene group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229950008257 ragaglitazar Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229960002101 secretin Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- 229950004704 tesaglitazar Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005557 thiazolylene group Chemical group 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 239000000777 urocortin Substances 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Definitions
- the present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.
- Glucagon is a key hormonal agent that, in co-operation with insulin, mediates ho- meostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
- Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells.
- Diabetes mellitus is a common disorder of glucose metabolism.
- the disease is characterized by hyperglycemia and may be classified as type 1 diabetes, the insulin- dependent form, or type 2 diabetes, which is non-insulin-dependent in character.
- Subjects with type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
- absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state.
- glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients.
- the action of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent gluca- gon-induced responses.
- the antagonist can be peptidic or non-peptidic in nature.
- Native glucagon is a 29 amino acid peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family. The receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
- Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred.
- non-peptide glucagon antagonists a quinoxa- line derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chem. Lett. 2(9):915-918 (1992)).
- WO 94/14426 (The Wellcome Foundation Limited) discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
- US 4,359,474 (Sandoz) discloses the glucagon inhibiting properties of 1 -phenyl pyrazole derivatives.
- US 4,374,130 (Sandoz) discloses substituted disilacyclohexanes as glucagon inhibiting agents.
- WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists.
- US 5,776,954 discloses substituted pyridyl pyrroles as gluca- gon antagonists and WO 98/21957, WO 98/22108, WO 98/22109 and US 5,880,139 (Merck & Co., Inc.) disclose 2,4-diaryl-5-pyridylirriidazoles as glucagon antagonists. Furthermore, WO 97/16442 and US 5,837,719 (Merck & Co., Inc.) disclose 2,5-substituted aryl pyrroles as glucagon antagonists.
- WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which are stated to possess glucagon antagonistic activity.
- Madsen et al. J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2-(benzimidazol- 2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antagonists.
- WO 99/01423 and WO 00/39088 disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists.
- WO 00/69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446 disclose further classes of glucagon antagonists.
- Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
- C ⁇ -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, n-pentyl, isopentyl, ⁇ eopentyl, ferf-pentyl, n-hexyl, isohexyl and the like.
- C 2 ⁇ -alkenyl represents a branched or straight hydrocar- bon group having from 2 to 6 carbon atoms and at least one double bond.
- groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-buta- dienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pent- enyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
- C 2 -6-alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atom's and at least one triple bond.
- groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
- C ⁇ -alkoxy refers to the radical -0-C 1-6 -alkyl wherein d ⁇ -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, iso- propoxy, butoxy, sec-butoxy, te/f-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
- C M -cycloalkyl represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
- C 4 ⁇ -cycloalkenyl represents a non-aromatic, carbocyclic group having from 4 to 8 carbon atoms containing one or two double bonds.
- Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopente ⁇ yI, 1-cyclohexenyl, 2-cyclo- hexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1 ,4-cycloocta- dienyl and the like.
- heterocyclyl represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
- aryl as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems.
- Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
- Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4- dihydronaphthyl, indanyl and the like.
- arylene as used herein is intended to include divalent, carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, divalent, carbocyclic, aromatic ring systems. Representative examples are phenylene, bi- phenylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, az- ulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
- Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthylene, 1 ,4-dihydronaphthylene and the like.
- aryloxy as used herein denotes a group -O-aryl, wherein aryl is as defined above.
- aroyl denotes a group -C(0)-aryl, wherein aryl is as defined above.
- C ⁇ -alkanoyl denotes a group -C(0)-C 1-6 -alkyl, wherein C L 6 -alkyl is as defined above.
- heteroaryl as used herein is intended to include aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
- furyl thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, ind
- Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
- Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
- heteroarylene as used herein is intended to include divalent, aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitro- gen, oxygen and sulfur.
- Heteroaryl is also in- tended to include the partially hydrogenated derivatives of the ring systems enumerated above.
- Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydro- benzofuranylene, pyrrolinylene, pyrazolinyle ⁇ e, indolinylene, oxazolidinylene, oxazolinylene, oxazepinylene and the like.
- Aryl-C ⁇ -alkyl means C 1-6 -alkyl or C 2 ⁇ - alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
- treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
- the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
- the patient to be treated is preferably a mammal, in particular a human being.
- the present invention relates to a compound of the general formula (I):
- n 0 or 1
- n 0, 1, 2 or 3
- R 4 is hydrogen, halogen or -(CH 2 ) 0 -OR 5 ,
- o 0 or 1
- R 5 is hydrogen, C 1-6 -alkyl, C . ⁇ -alkanoyl , aryl or aryl-C ⁇ -alkyl,
- R and R 2 independently are hydrogen, halogen or C 1-6 -alkyl, or R 1 and R 2 are combined to form a double bond
- R 3 is hydrogen, C 1-6 -alkyl or halogen, or R 3 and R 2 are combined to form a double bond to oxygen
- X is arylene or heteroaryiene, which may optionally be substituted with one or two groups R 6 and R 7 selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -N0 2 , -OR 8 , -NR 8 R 9 and C 1-6 -alkyl,
- R 8 and R 9 independently are hydrogen or d-e-alkyl
- Y is -C(O)-, -0-, -NR 10 -, -S-, -S(O)-, -S(0) 2 - or -CR 11 R 12 -,
- R 10 is hydrogen or C ⁇ -alkyl
- R 11 and R 2 independently are hydrogen, d-e-alkyl or hydroxy, or R 11 is combined with R 1 to form a double bond, and R 12 is hydrogen, C ⁇ . 6 -alkyl or hydroxy,
- Z is -C(0)-(CR 13 R 1 ) p -, -0-(CR 13 R 14 ) p -, -S-(CR 13 R 14 ) P -, -S(0)-(CR 13 R 14 ) p -, -S(0) 2 -(CR 13 R 14 ) p -, -NR 15 -(CR 13 R 1 ) P - or -(CR 13 R 14 ) P -,
- p 0, 1 or 2
- R 13 and R 14 independently are selected from hydrogen, -CF 3 , -OCF 3 and C ⁇ -B -alkyl,
- R 15 is hydrogen or C 1-6 -alkyl
- D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R 16 , R 17 , R 18 , R 19 , R 20 and R 21 , wherein
- R 16 , R 17 , R 18 and R 19 independently are
- aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -dOJOR 22 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -N0 2 , -OR 22 , -NR 22 R 23 and C 1-6 -alkyl,
- R 22 and R 23 independently are hydrogen, d- ⁇ -alkyl, a ⁇ /l-C ⁇ -alky! or aryl, or R 22 and R 23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
- a 0, 1 or 2
- c 1 or 2
- R 24 , R 25 , R 26 and R 27 independently are hydrogen, C 1-6 -alkyl or fluoro,
- R 20 and R 21 independently are hydrogen, C 1-5 -alkyl, C 3-8 -cycloalkyl or C 3-8 -cyclo- alkyl-C ⁇ -alkyl, E is
- heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -N0 2 , -OR 33 , - NR R 34 and C ⁇ . 6 -alkyl,
- R and R independently are hydrogen or d-e-alkyl
- R 33 and R 34 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
- R 28 and R 29 are as defined above, and R 30 , R 31 and R 32 are independently selected from
- aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , - N0 2 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
- R 35 and R 36 independently are hydrogen, d. 6 -alkyl or aryl
- R 35 and R 36 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
- t and I independently are 0, 1 , 2, 3, 4 or 5,
- R 37 and R 38 independently are hydrogen or Ci-e-alkyl
- A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- A is O
- A is
- A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- X is monocyclic arylene or heteroaryiene, which may optionally be substituted as defined for formula (I).
- R 6 and R 7 are as defined for formula (I).
- R 6 and R 7 are as defined for formula (I). In another embodiment, R s and R 7 are both hydrogen.
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- R ⁇ a , R , R* R J1 and R 32 are as defined for formula (I).
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- R 4B , R 29 , R J ⁇ , R 31 and R J2 are as defined for formula (I).
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- R , R J1 and R J4 are as defined for formula (I).
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- R 30 , R 31 and R 32 are as defined for formula (I).
- E is
- R ⁇ , Rf, R dU , R J1 and R J2 are as defined for formula (I).
- R , R 1 and R 32 are independently
- CL ⁇ -alk l which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 and -NR 35 R 36 , • or d-s-cycloalkenyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl,
- aryl, aryloxy or of which the aryl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -N0 2 , -R 35 , -NR 35 R 36 and C 1-6 -alkyl,
- R 35 and R 36 independently are hydrogen, d_s-alkyl or aryl
- R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
- R 30 , R 31 and R 32 are independently
- d-g-alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 and -NR 35 R 36 ,
- cyclohexyl or cyclohex-1-enyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 35 , -NR 35 R 36 and d. 6 -alkyl,
- phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 35 , -NR 35 R 36 and d. 6 -alkyl,
- phenoxy or benzyloxy of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 35 , -NR 35 R 36 and C 1-6 -alkyl, R and R 3 independently are hydrogen or
- R M and R" are both hydrogen, and R J1 is different from hydrogen
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- R 30 is as defined for formula (I).
- R 30 is
- halogen or • heteroaryl which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3) -N0 2 , -OR 35 , -NR 35 R 36 and C ⁇ -alkyl,
- R 35 and R 36 independently are hydrogen or d ⁇ -alkyl
- R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
- R 30 is
- thienyl which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF 3 , -N0 2 , -OR 35 , -NR 35 R 36 and C ⁇ -alkyl,
- R 35 and R 36 independently are hydrogen or C 1-5 -alkyl
- R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
- E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
- Y is -C(O)-, -0-, -S(0) 2 -, -NH- or -CH 2 -.
- Y is -CHR 11 -, wherein R 11 is combined with R 1 to form a double bond. In another embodiment, Y is -C(O)-.
- R 1 and R 2 are both hydrogen.
- R 1 and R 2 are combined to form a double bond.
- R 3 is hydrogen
- Z is -C(0)-(CR 13 R 1 ) p -, -0-(CR 13 R 1 ) p -, -NR 15 -(CR 13 R 14 ) p or -S(0) 2 - (CR 13 R 14 )p-, wherein p, R 13 , R 14 and R 15 are as defined for formula (I).
- Z is -NR 15 -(CR 13 R 14 ) p or -C(0)-(CR 3 R 14 ) p -, wherein p is as defined for formula (I), and R 3 and R 14 independently are selected from hydrogen, -CF 3 , -OCF 3 and C 1-6 -alkyl and R 15 is hydrogen.
- Z is -NH(CH 2 ) P or-C(0)-(CH 2 ) p -, wherein p is as defined for formula (I).
- Z is NH or -C(O)-.
- Z is -C(O)-.
- D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are as defined for formula (I).
- D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 16 , R 17 and R 18 are as defined for formula (I).
- R 15 , R 17 and R 18 are independently
- • d- ⁇ -alkyl which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF 3 , -OCF 3 , -OR 22 and -NR 22 R 23 , • d-8-cycloalkyl, which may optionally be substituted with one or more substituents selected from fluoro, -C(0)OR 24 , -CN, -CF 3 , -OCF 3 , -OR 22 , -NR 22 R 23 and C ⁇ -alkyl,
- aryl or aryloxy which may optionally be substituted with one or more substituents se- lected from halogen, -C(0)OR 22 , -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 22 , -NR 22 R 23 and
- R 22 and R 23 independently are hydrogen, C 1-6 -alkyl, aryl-C ⁇ -alkyl or aryl, or R 22 and R 23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
- a 0, 1 or 2
- c 1 or 2
- R 24 , R 25 , R 26 and R 27 independently are hydrogen, d- ⁇ -alkyl or fluoro.
- R 16 , R 17 and R 18 are independently
- R 18 is hydrogen, and R 17 and R 18 are different from hydrogen.
- R 16 and R 17 are hydrogen, and R 18 is different from hydrogen.
- the invention relates to a compound of the general formula (l 4 ):
- R 6 , R 7 , E and D are as defined for formula (I) or in any one of the above embodiments, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
- the invention relates to a compound of the general formula (l 5 ):
- R 6 , R 7 , E and D are as defined for formula (I) or in any one of the above embodiments, as well as any diastereomer or enantiomer or tautomeric form thereof including mix- tures of these or a pharmaceutically acceptable salt thereof.
- the invention relates to a compound of the general formula (l a):
- R ⁇ , R 7 , E and D are as defined for formula (I), as well as a ' ny diastereomer or enanti- omer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
- the invention relates to a compound of the general formula (l 5 b):
- R 6 , R 7 , E and D are as defined for formula (I), as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
- the invention relates to a compound of the general formula (1 6 ):
- R 6 , R 7 , E and D are as defined for formula (I) or in any one of the above embodiments, as well as any diastereomer or enantiomer or tautomeric form thereof including mix- tures of these or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.
- diastereomers when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.
- the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
- Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
- Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
- suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-amino- benzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
- compositions include the pharma- ceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
- metal salts include lithium, sodium, potassium, magnesium salts and the like.
- ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, fe/ -butyl-, tetramethylammonium salts and the like.
- pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
- the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.
- the acid addition salts may be obtained as the direct products of compound synthe- sis.
- the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
- the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such sol- vates are also contemplated as being within the scope of the present invention.
- the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances.
- prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible in vivo into the required compound of the formula (I).
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
- the invention also encompasses active metabolites of the present compounds.
- the compounds according to the present invention act to antagonize the action of glucagon and are accordingly useful for the treatment of disorders and diseases in which such an antagonism is beneficial.
- the compounds according to the present invention preferably have an IC 50 value of no greater than 5 ⁇ M, more preferably of less than 1 ⁇ M, even more preferred of less than 500 nM, such as of less than 100 nM as determined by the Glucagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.
- the present compounds may be applicable for the treatment of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndromes, syndrome X, type 1 diabetes, type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipo- proteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc.
- glucagon receptors may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secretions and to reverse intestinal hypomobility due to glucagon administration. They may also be useful as tool or reference molecules in labelled form eg radio- labelled in binding assays to identify new glucagon antagonists.
- the invention relates to a compound according to the invention for use as a medicament.
- the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.
- the pharmaceutical composition is preferably in unit dosage form comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the inven- tion.
- the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment of a disorder or disease, wherein a glucagon antagonistic action is beneficial.
- the invention also relates to a method for the treatment of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
- the present compounds are used for the preparation of a medicament for the treatment of any glucagon-mediated conditions and diseases.
- the present compounds are used for the preparation of a medicament for the treatment of hyperglycemia.
- the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
- the present compounds are effective in lowering the blood glucose, both in the fasting and the postprandial stage.
- the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT. In still another embodiment, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
- the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
- the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non- insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
- the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes.
- Such treatment is normally accompanied by insulin therapy.
- the present compounds are used for the preparation of a pharmaceutical composition for the treatment of obesity.
- the present compounds are used for the preparation of a pharmaceutical composition for the treatment of disorders of the lipid metabolism, such as dyslipidemia.
- the present compounds are used for the preparation of a pharmaceutical composition for the treatment of an appetite regulation or energy expenditure disorder.
- treatment of a patient with the present compounds is combined with diet and/or exercise.
- the present compounds are administered in combination with one or more further active substances in any suitable ratio(s).
- further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobe- sity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
- Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg Asp B28 human insulin, US 5,504,188 (Eli Lilly), eg Lys B28 Pro 829 human insulin, EP 368 187 (Aventis), eg Lantus®, all of which are incorporated herein by reference, GLP-1 and GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycemic agents.
- the orally active hypoglycemic agents include imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, ⁇ -glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, agents acting on the ATP-dependent potassium channel of the ⁇ -cells, eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), all of which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, insulin secretagogues, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
- PTPase inhibitors inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, activators of glucokinase (GK) such as those disclosed in WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478.WO 01/85706, WO 01/85707 and WO 02/08209 (Hoffman-La Roche), which are incorporated herein by reference, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.
- GK glucokinase
- PPAR peroxisome proliferator-activated receptor
- RXR
- the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 828 human insulin, Lys B2a Pro 629 human insulin, Lys B29 -(N ⁇ ( ⁇ -glutamyl-N ⁇ litocholyl) des (B30) human insulin, Lantus, or a mix-preparation comprising one or more of these.
- insulin or an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 828 human insulin, Lys B2a Pro 629 human insulin, Lys B29 -(N ⁇ ( ⁇ -glutamyl-N ⁇ litocholyl) des (B30) human insulin, Lantus, or a mix-preparation comprising one or more of these.
- the present compounds are administered in combination with a sulphonylurea, eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepride or glicazide.
- a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glimepride or glicazide.
- the present compounds are administered in combination with a biguanide, eg metformin.
- the present compounds are administered in combination with a meglitinide, eg repaglinide or nateglinide.
- the present compounds are administered in combination with a thiazolidinedione insulin sen ⁇ itizer, eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).
- the present compounds may be administered in combination with an insulin sensitizer such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, LY465608, MBX-102, CLX-0940, GW-501516, tesaglitazar (AZ 242) or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 such as ragaglitazar (NN 622 or (-)DRF 2725) (Dr.
- an insulin sensitizer such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, LY465608, MBX
- the present compounds are administered in combination with an ⁇ -glucosidase inhibitor, eg voglibose, emiglitate, miglitol or acarbose.
- an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS-67582, repaglinide or nateglinide.
- the present compounds are administered in combina- tion with an antihyperlipidemic agent or antilipidemic agent, eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simva ⁇ tatin, probucol or dextrothyroxine.
- an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simva ⁇ tatin, probucol or dextrothyroxine.
- the present compounds are administered in combination with more than one of the above-mentioned compounds, eg in combination with metformin and a sulphonylurea such as glibenclamide or glyburide; a sulphonylurea and acarbose; metformin and a meglitinide such as repaglinide; acarbose and metformin; a sul- fonylurea, metformin and troglitazone; a sulfonylurea, metformin and pioglitazone; a sulfony- lurea, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; a meglitinide such as repaglinide, metformin and troglitazone; a meglitinide such as repaglinide, metformin and pioglitazone; a meglitinide such as
- Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, H3 histamine antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita- lopram, serotonin
- the antiobesity agent is fenfluramine or dexfenfluramine.
- the antiobesity agent is sibutramine.
- the antiobesity agent is orlistat.
- the antiobesity agent is mazindol or phentermine.
- the present compounds may be administered in combination with one or more antihypertensive agents.
- antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington
- the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
- the phar- maceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
- compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
- compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropri- ate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
- Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
- Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
- Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
- a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
- the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
- a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
- typically doses are in the order of about half the dose employed for oral administration.
- the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
- One example is a base addition salt of a compound having the utility of a free acid.
- a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
- solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
- aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal admini- stration.
- the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
- Suitable pharmaceutical earners include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
- solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
- liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
- the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically ac- ceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
- the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
- the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
- the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
- the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
- a typical tablet that may be prepared by conventional tabletting techniques may con- tain:
- Active compound (as free compound or salt thereof) 5.0 mg
- the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
- DBU 1 ,8-diazabicyclo[5.4.0]undec-5-ene
- DCM dichloromethane
- DIPEA ⁇ /, ⁇ /-diisopropylethylamine
- DMF ⁇ , ⁇ /-dimethyl formamide
- NMP /V-methyl-2-pyrrolidinone
- TFA trifluoroacetic acid
- THF tetrahydrofuran
- HOBt 1 -hydroxybenzotriazole
- the instrument is controlled by HP Chemstation software.
- the HPLC pump is connected to two eluent reservoirs containing:
- HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
- HP LC/MSD ChemStation control software running on a HP Vectra computer is used for the instrument control and data acquisition.
- the HPLC pump is connected to two eluent reservoirs containing: A: 0.01% TFA in water
- the analysis is performed at room temperature by injecting 1 mL of the sample solution on the column which is eluted with a gradient of acetonitrile in 0.01% TFA.
- HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
- the Sciex Sample control software running on a Macintosh PowerPC 7200 com- puter is used for the instrument control and data acquisition.
- the HPLC pump is connected to four eluent reservoirs containing: A: Acetonitrile
- the requirements for the samples are that they contain approximately 500 ⁇ g/mL of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetoni- trile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)
- the analysis is performed at room temperature by injecting 20 ⁇ l of the sample solution on the column, which is eluted with a gradient of acetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions are used.
- the eluate from the column is passed through a flow splitting T-connector, which passed approximately 20 ⁇ l/min through approx. 1 m 75 ⁇ fused silica capillary to the API interface of API 100 spectrometer.
- the remaining 1.48 mL/min is passed through the UV detector and to the ELS de- tector.
- the detection data are acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.
- the instrument is controlled by HP Chemstation software.
- the HPLC pump is connected to two eluent reservoirs containing:
- the analysis is performed at 40 °C by injecting an appropriate volume of the sample (preferably 1 ⁇ l) onto the column which is eluted with a gradient of acetonitrile.
- HPLC conditions detector settings and mass spectrometer settings used are given in the following table.
- the title compound was prepared from indane and dichloromethyl methyl ether, using the same procedure as described above, providing a 1:2 mixture of indane-4-carbaldehyde and indane-5-carbaldehyde. The mixture was used for subsequent conversion to the chalcone
- 3,5-Dichlorobe ⁇ zoic acid (19,10 g, 100 mmol) was dissolved in dry THF (165 mL) and cooled to 0 °C in an ice bath. With vigorous stirring, 138 mL (210 mmol) of methyl lithium (1.6 M in diethyl ether) was added dropwise over a period of 30 min via syringe. After 1 hour the mixture was poured into ice-water (500 mL). The aqueous phase was extracted with diethyl ether (4 x 50 mL). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate (2 x 50 mL) and saturated aqueous sodium chloride (2 x 50 L).
- 6-Cyano-2,2,3,3-tetrafluoro-1.4-benzodioxene 35 g, 0.15 mol was dissolved in toluene (60 mL) and added to the reaction mixture. The mixture was heated to 80 °C for 1 hour without condenser to remove the diethyl ether. Additional 6- cyano-2,2,3,3-tetrafluoro-1.4-benzodioxene (25 g, 0.11 mol) was added and the mixture was heated at reflux temperature for 16 hours. The mixture was cooled with an ice bath and hydrochloric acid (6 M, 150 mL) was added carefully and the mixture was then heated to reflux for 1.5 hour.
- Step 1
- This reaction is known (Wang S.J., J. Am. Chem. Soc. 95, 1328, 1973) and is generally performed by stirring polystyrene resin loaded with a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopropyl- carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in the presence of a catalyst such as ⁇ /, ⁇ /-4-dimethylaminopyridine.
- a linker such as the Wang linker with a 4-10 molar excess of Fmoc-protected amino acid activated with a 2-5 molar excess of diisopropyl- carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl
- the ester- fication is carried out in solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
- solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
- the reactions are performed between 0 °C and 80 °C, prefera- bly between 20 °C to 40 °C.
- excess of reagent is removed by filtration.
- the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
- the resin bound product can be further dried and analyzed.
- Step 2 ⁇ /-Fluorenylmethylcarbonyl protecting group is removed by treating the resin bound derivative with a 20%-50% solution of a secondary amine such as piperidine in a polar solvent such as DMF or NMP (Carpino L, Han G., J. Org. Chem. 37, 3404, 1972).
- the reaction is performed between 20 °C to 180 °C, preferably between 20 °C to 40 °C.
- excess of reagent is removed by filtration.
- the resin is successively washed with solvent used in the reaction.
- the resulting resin bound intermediate is acylated with acid.
- the acylation is known (The combinatorial index, Ed. Bunin B. A., 1998, Acedemic press, p.
- acylation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
- aldehydes to activated double bonds is generally carried out by stirring the aldehyde with a compound that contains an activated dobbelt bond such as a substituted prope- none in the presence of a catalyst such as sodium or potassium cyanide or thiazolium salts such as 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide, 3-benzyl-5-(2-hydroxyethyl)-4- methyl-1 ,3-thiazolium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium bromide or vitamin Bi.
- a catalyst such as sodium or potassium cyanide or thiazolium salts
- a non-nucleophilic amine base such as triethyl amine, ⁇ , ⁇ /-diisopropylethylamine or DBU is added.
- the addition is carried out in a solvent such as dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
- the reactions are performed between 50 °C to 120 °C, preferably between 50 °C to 80 °C.
- excess of reagent is removed by filtration.
- the resin is successively washed with the solvent used in the reaction, followed by washing with methanol.
- the resin bound product can be further dried and analyzed.
- the reaction is known (The combinatorial index, Ed. Bunin B. A., 1998, Acedemic press, p. 21) and is generally performed by stirring the resin bound intermediate obtained in step 3 with a 50-95 % solution of TFA.
- the final cleavage is carried out in a solvent such as THF, DCM, 1 ,2 dichloroethane, 1 ,3-dichloropropane, toluene or a mixture or more of these.
- the reactions are performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
- the reaction is complete the product is removed by filtration.
- the resin is successively washed with DCM.
- the product and washings are collected.
- the solvent is removed and the product is dried in vacuo.
- the procedure is illustrated in the following example.
- Step 1 and Step 2 Resin bound 3-(4-formylbenzoylamino)propionic acid 3-(4-Formylbenzoylamino)propionic acid resin bound to a Wang resin (loading approximately 0.2 - 0.8 mmol/g) was synthesized according to the procedure described in WO 00/69810.
- Step 3 and Step 4 Preparation of 3-(4-f2-biphenyl-4-yl-4-oxo-4-(4-trifluoromethoxyphenyl)- butyryllbenzoylamino)propionic acid
- Step 1 - Step 3 Preparation of resin bound 3-(4-r2-f4-cvclohexylphenyl)-4-oxo-4-(4-trifluoro- methoxyphenvDbutyryllbenzoylaminolpropionic acid
- the compound was synthesized according to general procedure (B).
- Step 4 and Step 5 Preparation of 3-(4-r2-(4-cvclohexylphenyl)-4-oxo-4-(4-trifluoromethoxy- phenyl)but-2-enoyllbenzoylamino)propionic acid
- Step 6 Preparation of (Z)-3-f4-r2-(4-cvclohexylphenyl)-4-oxo-4-(4-trifluoromethoxyphenyl)- but-2-enovnbenzoylamino)propionic acid
- reaction mixture was filtered through a silica gel column eluted with DCM/methanol/acetic acid (90:9:1), and the solvent was removed by evaporation to yield an oil.
- the oil was washed with boiling heptane (4 mL) to remove unreacted 3-biphenyl-4-yl-1- (3-trifluoromethyiphenyl)propenone, and remaining material was purified on silica gel column eluted with DCM/methanol/acetic acid (95:4:1) to yield the title compound (30 mg, 9%).
- Step 1 wherein X, D, E, m, n and R 4 are as defined for formula (I), and Pg is a standard acid protecting group like methyl, ethyl, propyl, isopropyl, terf-butyl or benzyl.
- Pg is a standard acid protecting group like methyl, ethyl, propyl, isopropyl, terf-butyl or benzyl.
- the acylation of the amino group of of a protected amino acid is generally performed by activating the car- boxylic acid with diisopropyl-carbodiimide, dicyclohexylcarbodiimide or 1-[3-(dimethylamino)- propyl]-3-ethylcarbodiimide hydrochloride optionally in the presence of a side reaction inhibi- tor such as ⁇ /-hydroxybenzotriazole.
- the protected amino acid (protected eg as methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl ester) is then added to the activated carboxylic acid.
- a non-nucleophilic base such as triethylamine or diispropylethyl amine is added.
- the acylation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these.
- the reac- tion is generally performed between 0 °C to 80 °C, preferably between 20 °C to 40 °C.
- the product can be obtained by work-up procedures known to those skilled in the art.
- aldehydes to activated double bonds is generally carried out by stirring the alde- hyde with a compound that contains an activated dobbelt bond such as a substituted prope- none in the presence of a catalyst such as cyanid or thiazoliums salts such as 3,4-dimethyl- 5-(2-hydroxyethyl)thiazolium iodide, 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1 ,3-thiazolium bromide or vitamin B
- a non-nucleophilic amine base such as triethyl amine or DBU is added.
- the addition is carried out in a solvent such as ethanol, methanol, 1-propanol, 2-propa ⁇ ol, dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
- a solvent such as ethanol, methanol, 1-propanol, 2-propa ⁇ ol, dioxane, DMSO, NMP or DMF or a mixture of two or more of these.
- the reactions are performed between 50 °C to 120 °C, preferably between 50 °C to 80 °C.
- the product can be obtained by work-up procedures known to those skilled in the art.
- Step 3 Removal of the standard acid protecting groups depends on the nature of the protecting groups but has in general been described. (Protective Groups in Organic Chemistry. Greene T. W., Wuts P. G. M. 1999, Wiley-lnterscience, p. 377) The procedure is illustrated in the following examples.
- Step 1 3-(4-Formylbenzoylamino)-2r?-hvdroxypropionic acid methyl ester
- 4-formylbenzoic acid 7.5 g, 50 mmol
- DMF 80 mL
- 1 -Hydroxybenzotriazole, hydrate 8.11 g, 60 mmol, 1.2 eq
- ⁇ /'-(3- dimethylaminopropyl)- ⁇ /-ethylcarbodiimide hydrochloride (9.59 g, 50 mmol, 1 eq) were added.
- Step 2 Preparation of 3-f4-r4-(4-fe/ -butylphenyl)-2-(4-cvclohexylphenyl)-4-oxobutyrvn- benzoylamino)-2H-hvdroxypropionic acid ethyl ester
- Step 3 Pre p aration of 3- ⁇ 4-r4-(4-ten'-butylphenyl)-2-(4-cvclohexylphenyl)-4-oxobutyryll- benzoylamino)-2 ?-hvdroxypropionic acid
- Step 1 - Step 3 Preparation of 3-(4-r4-(4-terf-butylphenyl)-2-(4-cvclohexylphenvn-4- oxobutyrvnbenzoylamino)-2R-hvdroxypropionic acid
- Step 4 Preparation of 3- ⁇ 4-r4- ( 4-tert-Butylphenyl ) -2-(4-cvclohexylphenyl)-4-oxobut-2-enov ⁇ - benzoylamino ⁇ ft-hvdroxypropionic acid
- Step 5 Preparation of (Z)- 3-(4-r4-(4-fe f-butylphenyl)-2R-(4-cvclohexylphenyl)-4-oxobut-2- enoyl1benzoylamino)-2R-hvdroxypropionic acid
- Example 99 The compound of example 42 was also prepared according to the General procedure (F) as illustrated below: (Z)-3- ⁇ 4-[2-Biphenyl-4-yl-4-oxo-4-(4-trifluoromethoxyphenyl)but-2-enoyl]benzoylamino ⁇ -2 - hydroxypropionic acid
- Example 102 (General procedure (G)).
- the compound of example 65 was also prepared according to the General procedure (G) as illustrated below:
- Step 1 and Step 2 4-r2-r4-(2,2-dimethyl ⁇ ropy0phenyl1-4-oxo-4-(4-trifluoromethoxyphenyl)- butyryllbenzoic acid
- Step 4 and Step 5 Preparation of (Z)-3-(4-r2-f4-(2,2-Dimethyl-propyl)-phenvn-4-oxo-4-(4- trifluoromethoxy-phenyl)-but-2-enoyll-benzoylamino)propionic acid
- the mixture was stirred at 40 °C for 2 hours.
- the mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate.
- the organic phase was separated, washed with brine, dried (Na 2 S0 4 ) and evaporated.
- the residue was dissolved in a mixture of methanol (80 mL) and THF (20 mL) and sodium hydroxide (1.69 g; 42.3 mmol) in 10 mL of water was added.
- the mixture was stirred for 1.5 hours at room temperature.
- the mixture was concentrated to about 30 mL under reduced pressure and 40 mL of water was added.
- the pH was adjusted to 1.5 by addition of 1 M hydrochloric acid.
- Step 1 4-r4-(4-fen'-Butylphenv ⁇ -4-oxo-2-(4-trifluoromethoxyphenyl)butyrvnbenzoic acid methyl ester
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
- Indole Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
Cette invention, qui a trait à de nouveaux composés agissant comme antagonistes de l'action de l'hormone peptidique glucagon sur le récepteur du glucagon, porte, plus précisément, sur des antagonistes ou des agonistes inverses du glucagon.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK200101789 | 2001-12-03 | ||
DKPA200101789 | 2001-12-03 | ||
DKPA200201117 | 2002-07-18 | ||
DK200201117 | 2002-07-18 | ||
PCT/DK2002/000800 WO2003048109A1 (fr) | 2001-12-03 | 2002-11-28 | Nouveaux antagonistes de glucagon |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1463715A1 true EP1463715A1 (fr) | 2004-10-06 |
Family
ID=26069105
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02804158A Withdrawn EP1463715A1 (fr) | 2001-12-03 | 2002-11-28 | Nouveaux antagonistes de glucagon |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1463715A1 (fr) |
JP (1) | JP2005511683A (fr) |
AU (1) | AU2002365622A1 (fr) |
WO (1) | WO2003048109A1 (fr) |
Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2004210127B2 (en) | 2003-01-27 | 2009-10-01 | Merck Sharp & Dohme Corp. | Substituted pyrazoles, compositions containing such compounds and methods of use |
WO2005118542A1 (fr) * | 2004-05-28 | 2005-12-15 | Eli Lilly And Company | Antagonistes vis-a-vis des recepteurs du glucagon, elaboration et utilisations therapeutiques |
SI1758853T1 (sl) * | 2004-06-14 | 2010-05-31 | Lilly Co Eli | Antagonisti glukagonskega receptorja priprava inuporaba v terapiji |
US7622491B2 (en) * | 2004-08-13 | 2009-11-24 | Metabolex Inc. | Modulators of PPAR and methods of their preparation |
SI1856090T1 (sl) | 2005-02-11 | 2010-02-26 | Lilly Co Eli | Substituirani derivati tiofena kot antagonisti glukagonskega receptorja, priprava in terapevtske uporabe |
CN101146762A (zh) | 2005-03-21 | 2008-03-19 | 默克公司 | 取代的芳基和杂芳基衍生物 |
AU2006229904A1 (en) | 2005-03-30 | 2006-10-05 | Merck Sharp & Dohme Corp. | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
EP1962820A2 (fr) * | 2005-06-24 | 2008-09-03 | DSMIP Assets B.V. | Medicament pour le traitement du metabolisme de la glucose perturbee |
CA2614537A1 (fr) | 2005-07-26 | 2007-02-08 | Merck & Co., Inc. | Procede de synthese d'un pyrazole substitue |
TW200745031A (en) | 2005-10-13 | 2007-12-16 | Merck & Co Inc | Acyl indoles, compositions containing such compounds and methods of use |
PL1951658T3 (pl) | 2005-11-17 | 2013-02-28 | Lilly Co Eli | Antagoniści receptora glukagonu, preparatyka i zastosowania terapeutyczne |
DK1951661T3 (da) | 2005-11-17 | 2012-09-03 | Lilly Co Eli | Glucagonreceptorantagonister, fremstilling og terapeutiske anvendelser deraf |
CN101309894B (zh) | 2005-11-18 | 2012-10-03 | 伊莱利利公司 | 胰高血糖素受体拮抗剂、制备和治疗用途 |
CA2629172C (fr) | 2005-11-22 | 2014-05-06 | Eli Lilly And Company | Antagonistes de recepteur du glucagon, procedes de preparation et utilisations therapeutiques |
AU2006342059B2 (en) | 2005-11-23 | 2012-05-10 | Eli Lilly And Company | Glucagon receptor antagonists, preparation and therapeutic uses |
JP2009530381A (ja) | 2006-03-23 | 2009-08-27 | メルク エンド カムパニー インコーポレーテッド | グルカゴン受容体アンタゴニスト化合物、この化合物を含む組成物及び使用方法 |
US7935713B2 (en) | 2006-05-16 | 2011-05-03 | Merck Sharp & Dohme Corp. | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
TW200821284A (en) | 2006-10-03 | 2008-05-16 | Merck & Co Inc | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
KR20200123866A (ko) * | 2007-02-09 | 2020-10-30 | 메타베이시스 테라퓨틱스, 인크. | 글루카곤 수용체의 길항제 |
WO2009057784A1 (fr) * | 2007-11-01 | 2009-05-07 | Takeda Pharmaceutical Company Limited | Composé hétérocyclique |
CA2717138A1 (fr) * | 2008-03-05 | 2009-09-11 | Takeda Pharmaceutical Company Limited | Composes heterocycliques a 5 membres et heteroaryl bicyclique a action antagoniste du glucagon utiles pour le traitement du diabete |
CA2724294A1 (fr) * | 2008-05-16 | 2009-11-19 | Schering Corporation | Antagonistes du recepteur de glucagon, compostions et procede d'utilisation de ces composes |
CA2770298C (fr) * | 2008-08-13 | 2017-06-20 | Metabasis Therapeutics, Inc. | Antagonistes de glucagon |
CN101768149B (zh) * | 2008-12-30 | 2013-10-30 | 成都地奥制药集团有限公司 | 一类β-氨基酮(醇)衍生物及其用途 |
US20110281795A1 (en) | 2009-01-28 | 2011-11-17 | Songnian Lin | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
CL2009001796A1 (es) * | 2009-02-06 | 2011-09-16 | Takeda Pharmaceuticals Co | Compuestos derivados de heteroarilo-(benceno/heteroarilo) fusionados con actividad antagonista de glucagon; composicion farmaceutica; y su uso para suprimir la produccion de azucar y para la terapia o el tratamiento de la diabetes. |
WO2011027849A1 (fr) * | 2009-09-04 | 2011-03-10 | 武田薬品工業株式会社 | Composé hétérocyclique |
BR112013016033A2 (pt) | 2010-12-23 | 2018-06-05 | Pfizer | moduladores do receptor de glucagon |
WO2012107850A1 (fr) | 2011-02-08 | 2012-08-16 | Pfizer Inc. | Modulateur du récepteur de glucagon |
DK2714647T3 (en) * | 2011-05-23 | 2015-05-26 | Janssen Pharmaceutica Nv | Biphenyl derivatives useful as Glucagon receptor antagonists |
PL2714661T3 (pl) * | 2011-05-23 | 2016-03-31 | Janssen Pharmaceutica Nv | Pochodne kwasu pikolinamidopropanowego przydatne jako antagoniści receptora glukagonu |
RU2013157388A (ru) | 2011-07-22 | 2015-08-27 | Пфайзер Инк. | Хинолинильные модуляторы глюкагонового рецептора |
WO2013138753A1 (fr) | 2012-03-16 | 2013-09-19 | Fox Chase Chemical Diversity Center, Inc. | Promédicaments de riluzole et leur méthode d'utilisation |
ES2709824T3 (es) | 2013-02-22 | 2019-04-17 | Samumed Llc | Gamma-dicetonas como activadores de la ruta de señalización Wnt/beta-catenina |
US9649294B2 (en) | 2013-11-04 | 2017-05-16 | Merck Sharp & Dohme Corp. | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
JP2017519000A (ja) | 2014-06-12 | 2017-07-13 | リガンド・ファーマシューティカルズ・インコーポレイテッド | グルカゴンアンタゴニスト |
BR112017008809A2 (pt) * | 2014-11-05 | 2017-12-19 | Flexus Biosciences Inc | agentes imunorreguladores |
WO2017215586A1 (fr) * | 2016-06-14 | 2017-12-21 | 浙江海正药业股份有限公司 | Dérivés d'amide, leur procédé de préparation et leur utilisation en médecine |
EP3573961B1 (fr) * | 2017-01-27 | 2023-10-25 | Genfit | Modulateurs rorgamma et leurs utilisations |
US20210121422A1 (en) | 2018-02-13 | 2021-04-29 | Ligand Pharmaceuticals Incorporated | Glucagon receptor antagonists |
CN110357813A (zh) * | 2018-04-09 | 2019-10-22 | 信达生物制药(苏州)有限公司 | 一种新型吲哚胺2,3-双加氧酶抑制剂及其制备方法和用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6613942B1 (en) * | 1997-07-01 | 2003-09-02 | Novo Nordisk A/S | Glucagon antagonists/inverse agonists |
JP2004501897A (ja) * | 2000-06-23 | 2004-01-22 | ノボ ノルディスク アクティーゼルスカブ | グルカゴン拮抗薬/逆作用薬 |
-
2002
- 2002-11-28 AU AU2002365622A patent/AU2002365622A1/en not_active Abandoned
- 2002-11-28 EP EP02804158A patent/EP1463715A1/fr not_active Withdrawn
- 2002-11-28 WO PCT/DK2002/000800 patent/WO2003048109A1/fr active Application Filing
- 2002-11-28 JP JP2003549302A patent/JP2005511683A/ja not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO03048109A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2003048109A1 (fr) | 2003-06-12 |
AU2002365622A1 (en) | 2003-06-17 |
JP2005511683A (ja) | 2005-04-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2003048109A1 (fr) | Nouveaux antagonistes de glucagon | |
US6762318B2 (en) | Glucagon antagonists | |
US6881746B2 (en) | Glucagon antagonists/inverse agonists | |
US6562807B2 (en) | Glucagon antagonists/inverse agonists | |
WO2003097619A1 (fr) | Antagonistes/agonistes inverses de glucagon | |
EP1519723A1 (fr) | Nouveaux antagonistes/agonistes inverses du glucagon | |
US6649641B2 (en) | Glucagon antagonists/inverse agonists | |
JP2004501897A (ja) | グルカゴン拮抗薬/逆作用薬 | |
WO2003053938A1 (fr) | Nouveaux antagonistes/agonistes inverses du recepteur du glucagon | |
EP2305648A1 (fr) | Dérivés d'amide en tant qu'activateurs de la glucokinase | |
WO2004056763A2 (fr) | Nouveaux antagonistes du glucagon | |
WO2002040444A1 (fr) | Antagonistes/agonistes inverses de glucagon | |
WO2005058845A2 (fr) | Nouveaux antagonistes/agonistes inverses du glucagon | |
US20070015757A1 (en) | Novel Glucagon Antagonists/Inverse Agonists | |
US20040152750A1 (en) | Novel glucagon antagonists | |
EP1345891A1 (fr) | Antagonistes/agonistes inverses du glucagon | |
US6706744B2 (en) | Glucagon antagonists/inverse agonists | |
US6821960B2 (en) | Glucagon antagonists/inverse agonists | |
US20030212119A1 (en) | Novel glucagon receptor antagonists/inverse agonists | |
US20030229128A1 (en) | Glucagon receptor antagonists/inverse agonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20040705 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO SI |
|
17Q | First examination report despatched |
Effective date: 20071026 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: PFIZER INC. |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20100121 |