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WO2011142778A1 - Traitement du tcl et de la maladie d'alzheimer - Google Patents

Traitement du tcl et de la maladie d'alzheimer Download PDF

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Publication number
WO2011142778A1
WO2011142778A1 PCT/US2010/057287 US2010057287W WO2011142778A1 WO 2011142778 A1 WO2011142778 A1 WO 2011142778A1 US 2010057287 W US2010057287 W US 2010057287W WO 2011142778 A1 WO2011142778 A1 WO 2011142778A1
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WO
WIPO (PCT)
Prior art keywords
nifedipine
pharmaceutical composition
nitroso
lactam
effective amount
Prior art date
Application number
PCT/US2010/057287
Other languages
English (en)
Inventor
Mark Lovell
Bert Lynn
Original Assignee
The University Of Kentucky Research Foundation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from PCT/US2010/034721 external-priority patent/WO2010132671A1/fr
Application filed by The University Of Kentucky Research Foundation filed Critical The University Of Kentucky Research Foundation
Priority to AU2010353287A priority Critical patent/AU2010353287A1/en
Priority to EP10851531.3A priority patent/EP2568811A4/fr
Priority to CN2010800680043A priority patent/CN102984938A/zh
Priority to CA2799162A priority patent/CA2799162A1/fr
Priority to JP2013510067A priority patent/JP2013526518A/ja
Publication of WO2011142778A1 publication Critical patent/WO2011142778A1/fr

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Classifications

    • 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
    • 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
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

Definitions

  • AD Alzheimer's disease
  • MCI Mild Cognitive Impairment
  • Dr. Eschenbach explained that five drugs were approved for AD treatment— tacrine, rivastigmine, galantamine, donepezil, and memantine— the first four of which act by elevating acetylcholine levels in the brain, and the last of which is an antagonist of the N-methyl-D-aspartate receptor. Thus, Dr. Eschenbach pointed out that none of the five approved drugs have been shown to prevent or slow the underlying nerve degeneration in [AD] patients. He continued: "We await, together with the rest of the world, [] new drugs that may some day be able to treat the underlying cause of this insidious disease as well as other neurological diseases . . .”
  • the present invention encompasses the discovery that nifedipine and its oxidized or nitroso derivatives can effectively inhibit ⁇ 1 -40 generation, reduce ⁇ processing enzymes and inactivate related biochemical pathways, both in vitro and in vivo. More surprisingly, the present inventors discovered that a lactam (e.g., a compound of formula (Ic) or (Ic- ) such as NFD-L1) can also effectively inhibit ⁇ 1-40 generation, reduce ⁇ processing enzymes and inactivate related biochemical pathways, both in vitro and in vivo.
  • a lactam e.g., a compound of formula (Ic) or (Ic- ) such as NFD-L1
  • nitroso-nifedipine may likely be a pro-drug that converts stoichiometrically into lactam once administered in vivo.
  • the present invention provides, among other things, novel therapeutic methods and compositions, based on nifedipine and its oxidized or nitroso derivatives, and/or lactam and its derivatives (e.g., a compound of formula (Ic) or (Ic-/), e.g., NFD-L1), that can effectively treat, slow or prevent Mild Cognitive Impairment (MCI) and/or Alzheimer's disease, as well as delaying the progression from MCI to AD.
  • MCI Mild Cognitive Impairment
  • the present invention provides a pharmaceutical composition suitable for treating, slowing, or preventing a neurological disease in a human subject comprising a therapeutically effective amount of one or more therapeutic agents and a pharmaceutically acceptable carrier.
  • the neurological disease is a neurodegenerative disease.
  • the neurodegenerative disease is Mild Cognitive Impairment (MCI) and/or Alzheimer's disease.
  • MCI Mild Cognitive Impairment
  • a therapeutic agent is of formula (la) as defined and described herein.
  • a therapeutic agent is of formula (lb) as defined and described herein.
  • a therapeutic agent is of formula (Ic) as defined and described herein.
  • a therapeutic agent suitable for the invention is selected from the group consisting of nifedipine, oxidized nifedipine, nitroso-nifedipine, lactam (e.g., a compound of formula (Ic) or (Ic-/), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof.
  • a therapeutic agent suitable for the invention is a calcium channel blocker.
  • a therapeutic agent suitable for the invention is not a calcium channel blocker.
  • a therapeutic agent suitable for the invention increases calcium influx.
  • a therapeutic agent suitable for the invention comprises nifedipine. In some embodiments, a therapeutic agent suitable for the invention comprises oxidized nifedipine. In some embodiments, a therapeutic agent suitable for the invention comprises nitroso-nifedipine. In some embodiments, a therapeutic agent suitable for the invention comprises lactam (e.g., a compound of formula (Ic) or (Ic-/), e.g., NFD-L1). In some embodiments, a therapeutic agent suitable for the invention comprises a mixture of nitroso-nifedipine, oxidized nifedipine, and nifedipine.
  • a therapeutic agent suitable for the invention comprises a mixture of nitroso-nifedipine and lactam (e.g., a compound of formula (Ic) or (Ic-z), e.g., NFD-L1).
  • a therapeutic agent suitable for the invention comprises a mixture of lactam (e.g., a compound of formula (Ic) or (lc-i), e.g., NFD-L1), oxidized nifedipine, and nifedipine.
  • a therapeutic agent suitable for the invention comprises 55% nitroso-nifedipine, 11% oxidized nifedipine, and 34% nifedipine.
  • a therapeutic agent suitable for the invention comprises one or more (e.g., two, three, four) of lactam (e.g., a compound of formula (Ic) or (lc-i), e.g., NFD-L1), nitroso-nifedipine, oxidized nifedipine, and nifedipine.
  • lactam e.g., a compound of formula (Ic) or (lc-i), e.g., NFD-L1
  • nitroso-nifedipine oxidized nifedipine
  • various therapeutic agents described herein further comprises thyroxine (T4) and/or triiodothyronine (T3).
  • a therapeutic agent suitable for the invention comprises nifedipine, oxidized nifedipine, nitroso-nifedipine, thyroxine (T4) and/or triiodothyronine (T3).
  • a pharmaceutical composition according to the present invention comprises a therapeutic agent in a therapeutically effective amount of about 0.01 to about 1000 mg (e.g., about 0.01 to about 200 mg, about 0.01 to about 100 mg, about 0.1 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.5 mg, about 0.01 to about 0.1 mg) per dose.
  • a therapeutic agent in a therapeutically effective amount of about 0.01 to about 1000 mg (e.g., about 0.01 to about 200 mg, about 0.01 to about 100 mg, about 0.1 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.5 mg, about 0.01 to about 0.1 mg) per dose.
  • a pharmaceutical composition according to the present invention comprises nitroso-nifedipine in a therapeutically effective amount of about 10 mg to 2.5 g (e.g., about 10 mg to 2.0 g, about 10 mg to 1.5 g, about 10 to about 1000 mg, about 10 mg to about 500 mg) per dose.
  • a pharmaceutical composition according to the present invention comprises a therapeutic agent in a therapeutically effective amount, wherein the therapeutically effective amount is insufficient to induce an adverse event in a human subject.
  • an adverse event is liver toxicity.
  • a pharmaceutical composition according to the present invention comprises a therapeutic agent in a therapeutically effective amount, wherein the therapeutically effective amount is insufficient to induce an adverse event in a human subject, wherein the agent is nitroso- nifedipine and the adverse event is liver toxicity.
  • a pharmaceutical composition according to the present invention is formulated for oral, subcutaneous, intravenous, transdermal, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, or rectal administration.
  • a pharmaceutical composition according to the present invention is formulated for oral administration.
  • a pharmaceutical composition according to the invention is formulated for immediate or extended release.
  • the present invention provides a method for treating, slowing, or preventing a neurological disease in a human subject, the method comprising administering to the subject who is suffering from or susceptible to a neurological disease a therapeutic agent, such that at least one symptom or feature associated with the neurological disease is reduced in abundance, intensity, severity, or frequency, or has delayed onset.
  • a neurological disease is a neurodegenerative disorder.
  • the present invention provides a method for treating, slowing, or preventing Mild Cognitive Impairment (MCI) and/or Alzheimer's disease in a human subject, the method comprising administering to a subject who is suffering from or susceptible to MCI or Alzheimer's disease a therapeutically effective amount of one or more therapeutic agents, such that at least one symptom or feature associated with the MCI or Alzheimer's disease is reduced in abundance, intensity, severity, or frequency, or has delayed onset.
  • MCI Mild Cognitive Impairment
  • a symptom or feature is cognitive decline, production of amyloid beta protein, beta-secretase activity, gamma-secretase activity, paired helical filaments, phosphorylated tau protein in the brain, and/or an immune or inflammatory condition in the central nervous system.
  • an immune or inflammatory condition in the central nervous system is viral meningitis, viral encephalitis, fungal meningitis, fungal encephalitis, multiple sclerosis, schizophrenia, myasthenia gravis, or Charcot joint.
  • production of amyloid beta protein comprises production of ⁇ 1-40.
  • production of amyloid beta protein comprises production of ⁇ 1-42.
  • production of amyloid beta protein is reduced by increasing an alpha-secretase activity.
  • alpha-secretase activity is ADAM- 10 activity.
  • the gamma-secretase activity is reduced by inhibiting presenilin-1 (PS-1), nicastrin, APH-1 and/or PEN-2 activity.
  • the gamma-secretase activity is reduced by inhibiting orphan G-coupled receptor 3 (GPCR-3) activity.
  • GPCR-3 G-coupled receptor 3
  • an immune or inflammatory condition is reduced by decreasing the level of one or more cytokines (e.g., IL-1, IL-6, TNF-a) in the central nervous system.
  • cytokines e.g., IL-1, IL-6, TNF-a
  • a therapeutically effective amount of an agent according to the present invention is sufficient to increase a glutamate transporter level in the brain of a human subject.
  • a glutamate transporter level is a glial glutamate transporter EAAT2 level.
  • a therapeutically effective amount of an agent according to the present invention is insufficient to induce an adverse event in a human subject.
  • an adverse event is liver toxicity.
  • a therapeutic agent used in a method according to the present invention is of formula (la) as defined and described herein. In some embodiments, a therapeutic agent used in a method according to the invention is of formula (lb) as defined and described herein. In some embodiments, a therapeutic agent used in a method according to the invention is of formula (Ic) as defined and described herein.
  • a suitable therapeutic agent is selected from the group consisting of nifedipine, oxidized nifedipine, nitroso-nifedipine, lactam (e.g., a compound of formula (Ic) or (Ic- ), e.g., NFD- Ll), thyroxine (T4), triiodothyronine (T3) and combinations thereof.
  • a suitable therapeutic agent is a calcium channel blocker.
  • a suitable therapeutic agent is not a calcium channel blocker.
  • a suitable therapeutic agent increases calcium influx.
  • a suitable therapeutic agent comprises nifedipine. In some embodiments, a suitable therapeutic agent comprises oxidized nifedipine. In some embodiments, a suitable therapeutic agent comprises nitroso-nifedipine. In some embodiments, a suitable therapeutic agent comprises lactam (e.g., a compound of formula (Ic) or (Ic-/), e.g., NFD-L1). In some embodiments, a suitable therapeutic agent used in a method according to the present invention comprises a mixture of nitroso-nifedipine, oxidized nifedipine, and nifedipine.
  • a suitable therapeutic agent comprises a mixture of nitroso-nifedipine and lactam (e.g., a compound of formula (Ic) or (Ic-/), e.g., NFD-L1).
  • a suitable therapeutic agent comprises a mixture of lactam (e.g., a compound of formula (Ic) or (Ic-/, e.g., NFD-L1), oxidized nifedipine, and nifedipine.
  • a suitable therapeutic agent used in a method according to the present invention comprises 55% nitroso-nifedipine, 1 1% oxidized nifedipine, and 34% nifedipine.
  • a suitable therapeutic agent comprises one or more (e.g., two, three, four) of lactam (e.g., a compound of formula (Ic) or (lc-i), e.g., NFD-L1), nitroso-nifedipine, oxidized nifedipine, and nifedipine.
  • lactam e.g., a compound of formula (Ic) or (lc-i), e.g., NFD-L1
  • suitable agents described herein further comprises T3/T4.
  • an suitable agent used in a method of the present invention comprising nifedipine, oxidized nifedipine, and/or nitroso-nifedipine further comprises thyroxine (T4) and/or triiodothyronine (T3).
  • a method according to the present invention administers to a subject in need of treatment a therapeutic agent in a therapeutically effective amount of about 0.01 to about 1000 mg (e.g., about 0.01 to about 200 mg, about 0.01 to about 100 mg, about 0.1 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.5 mg, about 0.01 to about 0.1 mg) per dose.
  • a therapeutic agent in a therapeutically effective amount of about 0.01 to about 1000 mg (e.g., about 0.01 to about 200 mg, about 0.01 to about 100 mg, about 0.1 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.5 mg, about 0.01 to about 0.1 mg
  • a method according to the present invention administers to a subject in need of treatment a therapeutic agent comprising nitroso-nifedipine in a therapeutically effective amount of about 10 mg to about 2.5 g (e.g., about 10 mg to about 2.0 g, about 10 mg to about 1.5 g, about 10 mg to about 1000 mg, or about 10 mg to about 500 mg) per dose.
  • an agent used in a method according to the present invention is administered by oral, subcutaneous, intravenous, transdermal, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, or rectal administration.
  • an agent used in a method according to the present invention is administered orally.
  • an agent is administered monthly, bi-weekly, or weekly. In some embodiments, according to a method of the present invention, an agent is administered daily. In some embodiments, according to a method of the present invention, an agent is administered twice daily, three times daily, or four times daily.
  • a subject treated by a method of the present invention has a diminished or elevated level of a biomarker (e.g., a protein biomarker complex) as compared to a control.
  • a suitable biomarker is a protein biomarker complex comprising at least one of a transthyretin protein and/or a prostaglandin-H2 D- isomerase protein, and at least one second, different protein selected from a transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu— Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, and/or serotransferrin protein.
  • a suitable protein biomarker complex comprises prostaglandin-D2-synthase and transthyretin (PDS/TTR complex).
  • a suitable biomarker comprises one or more of (i) beta amyloid 40 ( ⁇ 40), (ii) beta amyloid 42 ( ⁇ 42), (iii) the ratio of ⁇ 40 to ⁇ 42, and (iv) the ratio of phosphorylated tau to total tau.
  • a biomarker is determined in a fluid sample (e.g., CSF, serum, whole blood, blood plasma, urine, ascitic fluid, saliva, tissue effusion, lavage, and combinations thereof) obtained from the subject.
  • a fluid sample e.g., CSF, serum, whole blood, blood plasma, urine, ascitic fluid, saliva, tissue effusion, lavage, and combinations thereof
  • a suitable control is indicative of a level of the biomarker in a subject selected from the group consisting of a healthy individual, a patient suffering from Alzheimer's disease with a pre-determined stage, the subject before the treatment, and combinations thereof.
  • a subject to be treated has a test score indicative of cognitive impairment.
  • a test score indicative of cognitive impairment is an MMSE score (e.g., lower than 27, e.g., 21-26).
  • a test score indicative of cognitive impairment is a CDR score (e.g., above 0, e.g., 0.5, e.g., 1).
  • a method according to the invention further includes a step of first determining the therapeutically effective amount of the therapeutic agent based on the level of a biomarker and/or a cognitive test score.
  • the invention provides a solid oral dosage form comprising nitroso-nifedipine and nifedipine, and wherein the mass ratio of nitroso- nifedipine to nifedipine is at least about 1 : 1 (e.g., at least about 2: 1, at least about 4: 1, at least about 8: 1, at least about 16: 1, at least about 32: 1, at least about 64: 1, at least about 100: 1, at least about 200: 1, at least about 500: 1, or at least about 1000: 1).
  • a solid oral dosage form according to the present invention further comprises one or more pharmaceutically acceptable excipients (e.g., a binder, a buffer, a diluent, a dispersant, an emollient, a film-forming agent, a glidant, a light-blocking agent, a preservative, a solvent, a stabilizing agent, a surfactant, a suspending agent, and/or a tonicity agent).
  • a solid dosage form is for controlled or extended release.
  • a solid dosage form is for immediate release.
  • the invention provides benzo[c][2,7]naphthyridine-
  • provided compounds are of the general formula (Ic):
  • R 1 and R 2 are independently an optionally substituted group selected from Ci_6 aliphatic, C e heteroaliphatic, aryl, heteroaryl, or cyano;
  • R 3 is an optionally substituted group selected from Ci_6 aliphatic, C e heteroaliphatic or aryl;
  • R 5 is halogen, optionally substituted Ci_6 aliphatic, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, or nitroso;
  • n 0, 1, 2, or 3.
  • provided compounds are of formula (Ic- ):
  • R 1 and R 2 are independently Ci_6 aliphatic or cyano;
  • R 3 is Ci-6 aliphatic
  • R 5 is halogen, Ci_6 aliphatic, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, or nitroso;
  • n 0, 1, 2, or 3.
  • an inventive compound is NFD-L1.
  • the present invention also provides pharmaceutical compositions containing a compound described herein (e.g., a compound of formula Ic or left and methods of use.
  • the present invention provides a method of treating, slowing, or preventing a neurological disease in a human subject by administering to a subject who is suffering from or susceptible to a neurological disease a compound described herein (e.g., such as a compound of formula Ic or Ic- ).
  • the present invention provides a method of treating, slowing, or preventing a neurodegenerative disease in a human subject by administering to a subject who is suffering from or susceptible to a neurodegenerative disease a compound described herein (e.g., such as a compound of formula Ic or Ic-i).
  • a compound described herein e.g., such as a compound of formula Ic or Ic-i
  • the present invention provides a method of treating, slowing, or preventing Mild Cognitive Impairment (MCI) and/or Alzheimer's disease in a human subject by administering to a subject who is suffering from or susceptible to MCI or Alzheimer's disease a compound described herein (e.g., such as a compound of formula Ic or Ic-i).
  • MCI Mild Cognitive Impairment
  • the invention provides a method of inhibiting beta secretase (BACE) in a human subject comprising administering to the human subject a compound described herein (e.g., such as a compound of formula Ic or Ic-i).
  • BACE beta secretase
  • the invention provides a method of modulating an inflammatory condition in the central nervous system of a human subject by administering to the human subject a compound described herein (e.g., such as a compound of formula Ic or Ic-i).
  • Figure 1 illustrates an exemplary Western blot analysis of the PDS/TTR complex expressed in cell culture medium by control epithelial cells, control epithelial cells treated with acrolein, and late stage AD epithelial cells.
  • Figure 2 illustrates exemplary survival data for cortical neurons treated with medium from control epithelial cells or AD epithelial cells.
  • Figure 3 illustrates exemplary results indicating that PHF 1 immunopositivity was detected in SY5Y cells resulting from exposure to the PDS/TTR protein complex.
  • Figure 4 illustrates exemplary Western blot data showing reduction of the
  • Figure 5 summarizes the numbers of PDS/TTR-positive cells determined by immunostaining in cultures treated with acrolein, acrolein plus T3/T4, acrolein plus nifedipine mixture (nitroso nifedipine 55%, oxidized nifedipine 11% and nifedipine 34%) and acrolein plus nifedipine mix and T3/T4.
  • Figure 6 illustrates that nifedipine mix does not function as a calcium channel blocker compared to fresh nifedipine as determined by confocal microscopy and a calcium fluorescent dye.
  • Figure 7 illustrates exemplary results indicating that inflammatory cytokine production was inhibited by nifedipine mix.
  • Figure 8 illustrates exemplary results indicating that inflammatory cytokine production was inhibited by NFD-L1.
  • Figure 9 illustrates quantification of PHF-1 immunostaining for SY5Y cultures treated with medium from epithelial cells treated with acrolein and combinations of nifedipine, analogs, mixtures and T3/T4.
  • Figure 10 illustrates exemplary results indicating that ABi_ 4 2 generation is inhibited by nifedipine, oxidized nifedipine, nitroso nifedipine and T3/T4.
  • Figure 1 1 illustrates exemplary results indicating effect of nifedipine, nifedipine analogs and nifedipine mix, with and without T3/T4 on ⁇ i_ 4 2 production from H4 cells.
  • Figure 12 illustrates exemplary results indicating effects of known calcium channel blockers such as Amilodpine, Dilitiazem, Felodipine, Isradipine, Nicardipine, and Nimodipine on ⁇ 1-42 generation in H4 neuroglioma cultures.
  • known calcium channel blockers such as Amilodpine, Dilitiazem, Felodipine, Isradipine, Nicardipine, and Nimodipine
  • Figure 13 illustrates exemplary results indicating effects of NFD-L1 on ⁇ 1-
  • Figure 14 illustrates exemplary results indicating that nitroso-nifedipine significantly inhibits BACE activity.
  • Figure 15 illustrates exemplary results indicating that NFD-Ll significantly inhibits BACE activity.
  • Figure 16 illustrates exemplary results indicating the effect of nifedipine mix on PS-1, PEN-2, BACE-1 and Nicastrin, with and without T3/T4.
  • Figure 17 illustrates exemplary results indicating the effect of nifedipine, nifedipine mix and/or T3/T4 on ABl-40 generation and certain ABl-40 processing enzymes in a mouse model.
  • Figure 18 illustrates exemplary results indicating that treatment with nitroso- nifedipine leads to a decrease in levels of ABl-40 in a mouse model.
  • Figure 19 illustrates exemplary results indicating that nifedipine, nifedipine mix and/or T3/T4 reduced GPCR-3 levels in H4 cultures or in mice treated acutely with drugs.
  • the GPCR-3 levels were determined using Western blot analysis.
  • Figure 20 illustrates exemplary results indicating the effect of other classes of blood pressure drugs on the levels of GPCR-3 in H4 cultures with and without T3/T4.
  • Figure 21 illustrates exemplary results showing survival of H4 cells after treatment with increasing concentrations of nitroso-nifedipine.
  • Figure 22 summarizes exemplary effects of nitroso-nifedipine on levels of enzymes involved in AB processing.
  • Figure 23 summarizes exemplary effects of NFD-L1 on levels of enzymes involved in AB processing.
  • Figure 24 summarizes exemplary effects of nitroso-nifedipine on levels of enzymes involved in AB processing in a mouse model.
  • Figure 25 summarizes exemplary effects of NFD-L1 on levels of enzymes involved in AB processing in a mouse model.
  • Figure 26 illustrates exemplary results indicating the effect of nifedipine, nifedipine mix and/or T3/T4 on the levels of enzymes involved in Tau phosphorylation measured in the mouse brains treated with corresponding compounds.
  • Figure 27 illustrates exemplary effects of nifedipine and nitroso-nifedipine on glutamate transporter levels.
  • Figure 28 illustrates exemplary results indicating that nitroso-nifedipine does not induce liver damage in mice.
  • Figure 29 illustrates exemplary trajectories fitted according to the NLMIXED model of MMSE verse age based on a human association study.
  • Figure 30 illustrates exemplary results indicating levels of ⁇ 1-42 and ⁇ processing enzymes such as PS-1, Nicas, BACE, APH-1 and PEN-2 in front lobe specimens of subjects from a neuropsychological test score association study who came to autopsy. 4 subjects were on calcium channel blockers, including nifedipine and 4 subjects were not on any calcium channel blocker. AB levels determined using Invitrogen ELISAs. Protein levels determined using Western blot analysis and antibodies specific to each protein. [0056] Figure 31 illustrates exemplary results indicating enzyme levels involved in
  • Figure 32 illustrates exemplary results indicating that treatment of H4 neuroglioma cultures with nitroso-nifedipine leads to a significant increase in calcium influx as compared to control.
  • Figure 33 illustrates exemplary results from a photochemical synthesis of nitros o-nifedipine.
  • Figure 34 illustrates exemplary results from a synthesis of NFD-L1.
  • Alzheimer 's patient As used herein, the terms “Alzheimer's patient,” “AD patient,” and “individual diagnosed with AD” all refer to an individual who has been diagnosed with AD or has been given a probable diagnosis of Alzheimer's Disease (AD).
  • AD Alzheimer's Disease
  • animal refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and/or a clone.
  • mammal e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig.
  • Bio fluid sample encompasses a variety of fluid sample types obtained from an individual and can be used in a diagnostic or monitoring assay.
  • the term encompasses whole blood, blood serum or blood plasma, cerebrospinal fluid (CSF), urine and other liquid samples of biological origin.
  • CSF cerebrospinal fluid
  • the term also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components, such as proteins or polynucleotides.
  • Combination therapy refers to those situations in which two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents.
  • Control has its art-understood meaning of being a standard against which results are compared. Typically, controls are used to augment integrity in experiments by isolating variables in order to make a conclusion about such variables.
  • a control is a reaction or assay that is performed simultaneously with a test reaction or assay to provide a comparator. In one experiment, the "test” (i.e., the variable being tested) is applied. In the second experiment, the "control,” the variable being tested is not applied.
  • a control is a historical control (i.e., of a test or assay performed previously, or an amount or result that is previously known).
  • a control is or comprises a printed or otherwise saved record.
  • a control may be a positive control or a negative control.
  • Dosing regimen refers to a set of unit doses (at least one and often more than one) that are administered individually separated by periods of time. The recommended set of doses (i.e., amounts, timing, route of administration, etc.) for a particular therapeutic agent constitutes its dosing regimen.
  • a "functional" biological molecule is a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.
  • inhibiting a protein or a gene refers to processes or methods of decreasing or reducing activity and/or expression of a protein or a gene of interest.
  • inhibiting a protein or a gene refers to reducing expression or a relevant activity of the protein or gene by at least 10% or more, for example, 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90% or more, or a decrease in expression or the relevant activity of greater than 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 50-fold, 100-fold or more as measured by one or more methods described herein or recognized in the art.
  • in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.
  • in vivo refers to events that occur within a multi-cellular organism such as a non-human animal.
  • Isolated refers to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and/or in an experimental setting), and/or (2) produced, prepared, and/or manufactured by the hand of man. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, substantially 100%, or 100% of the other components with which they were initially associated.
  • isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, substantially 100%, or 100% pure.
  • a substance is "pure” if it is substantially free of other components.
  • isolated cell refers to a cell not contained in a multi-cellular organism.
  • an "individual with EAD (early or moderate Alzheimer's disease)” is an individual who demonstrate the following criteria: 1) a decline in cognitive function for a previous higher level, 2) declines in one or more areas of cognition in addition to memory, 3) a clinical dementia rating scale score of 0.5 to 1, and 4) a clinical examination that excluded other causes of dementia.
  • an "individual with LAD (severe or late stage Alzheimer's disease)" is an individual who meets the standard clinical diagnostic criteria for probable AD (McKhann et al. Neurology 34:939-48 (1984).
  • Lactam As used herein, a "lactam” is a cyclic amide. Typically, prefixes indicate how many carbon atoms (apart from the carbonyl moiety) are present in the ring: ⁇ - lactam (2 carbon atoms outside the carbonyl, 4 ring atoms in total), ⁇ -lactam (3 and 5), ⁇ - lactam (4 and 6).
  • a lactam suitable for the invention is defined by formula (Ic) or formula (Ic-z).
  • a lactam suitable for the invention is NFD-L1.
  • Reference value can be an absolute value; a relative value; a value that has an upper and/or lower limit; a range of values; an average value; a median value, a mean value, or a value as compared to a particular control or baseline value.
  • a reference value can be based on an individual sample value, such as for example, a value obtained from a sample from the individual with AD, MCI or cognitive impairment, but at an earlier point in time, or a value obtained from a sample from an AD patient other than the individual being tested, or a "normal" individual, that is an individual not diagnosed with AD.
  • Neurological disease refers to a disease or disorder of the central nervous system. Neurological diseases include multiple sclerosis, neuropathies, and neurodegenerative disorders such as AD, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, mild cognitive impairment (MCI) and frontotemporal dementia.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MCI mild cognitive impairment
  • Additional exemplary neurological diseases include epilepsy, convulsive disorder, pain, anxiety, depression, schizophrenia, post-anesthesia cognitive decline, opioid tolerance, drug abuse, alcohol abuse, schizophrenia, neuroleptic malignant syndrome, Tourette's syndrome, Pick's Disease, dementia, delirium, neurodegeneration in Down Syndrome, Familial British Dementia, Familial Danish Dementia, Korsakoff s disease, olivopontocerebellar atrophy, HlV-induced dementia and blindness, multi-infarct dementia, hereditary motor and sensory neuropathies (HMSN, also known as peroneal muscular atrophy or Charcot-Marie-Tooth disease), diabetic polyneuropathy, olivopontocerebellar atrophy, age-onset neurological deterioration, alcoholic polyneuropathy, tinnitus, and
  • Normal individual As used herein, a "Normal" individual or “healthy” individual refers to an individual who has or would be assessed by a physician as not having AD or MCI, and has an Mini-Mental State Examination (MMSE) (referenced in Folstein et al, J. Psychiatr. Res 1975; 12: 1289-198) score or would achieve a MMSE score in the range of 25-30.
  • MMSE Mini-Mental State Examination
  • a “Normal” individual is generally age-matched within a range of 5 to 10 years, including but not limited to an individual that is age-matched, with the individual to be assessed.
  • Protein refers to a polypeptide (i.e., a string of at least two amino acids linked to one another by peptide bonds). Proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and/or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete polypeptide chain as produced by a cell (with or without a signal sequence), or can be a characteristic portion thereof. Those of ordinary skill will appreciate that a protein can sometimes include more than one polypeptide chain, for example linked by one or more disulfide bonds or associated by other means.
  • Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, etc.
  • proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof.
  • the term "peptide" is generally used to refer to a polypeptide having a length of less than about 100 amino acids.
  • Subject refers to any organism to which compositions in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.).
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • Susceptible to An individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • Therapeutically effective amount As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount that is sufficient, when
  • therapeutic agent refers to any agent that, when administered to a subject, has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect.
  • therapeutic agent and “agent” are used inter-changeably.
  • Treating refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and/or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • the compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Aliphatic denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cycloaliphatic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-4 carbon atoms, and in yet other embodiments aliphatic groups contain 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,
  • Alkenyl denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon- carbon double bond by the removal of a single hydrogen atom. In certain embodiments, alkenyl contains 2-6 carbon atoms. In certain embodiments, alkenyl contains 2-5 carbon atoms. In some embodiments, alkenyl contains 2- ⁇ carbon atoms. In another embodiment, alkenyl contains 2-3 carbon atoms. Alkenyl groups include, for example, ethenyl ("vinyl”), propenyl ("allyl”), butenyl, l-methyl-2-buten-l-yl, and the like.
  • Alkyl refers to a monovalent saturated, straight- or branched-chain hydrocarbon radical derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. In some embodiments, alkyl contains 1-5 carbon atoms. In another embodiment, alkyl contains 1-4 carbon atoms. In still other embodiments, alkyl contains 1-3 carbon atoms. In yet another embodiment, alkyl contains 1-2 carbons.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso- pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n- undecyl, dodecyl, and the like.
  • Alkynyl refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon- carbon triple bond by the removal of a single hydrogen atom. In certain embodiments, alkynyl contains 2-6 carbon atoms. In certain embodiments, alkynyl contains 2-5 carbon atoms. In some embodiments, alkynyl contains 2- ⁇ carbon atoms. In another embodiment, alkynyl contains 2-3 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl ("propargyl”), 1-propynyl, and the like.
  • amino refers to a group of the formula (- [0096]
  • Alkoxy refers to a "substituted hydroxyl" of the formula
  • R 1 is an alkyl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • alkylamino refers to a "substituted amino" of the formula (-NR h 2), wherein R h is, independently, a hydrogen or an alkyl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • aryl refers to an optionally substituted monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • Cycloaliphatic The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”,
  • Carbocyclo or “carbocyclic”, used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 10 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • the cycloalkyl has 3-6 carbons.
  • cycloaliphatic also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane, where the radical or point of attachment is on an aliphatic ring.
  • Cyano refers to a group of the formula (-
  • Halogen refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
  • fluorine fluoro, -F
  • chlorine chloro, -CI
  • bromine bromine
  • iodine iodo, -I.
  • Heteroaliphatic - As used herein, the terms "heteroaliphatic" or
  • heteroaliphatic group denote an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic ("heterocyclic") and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
  • heteroaliphatic groups contain 1-6 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen and sulfur.
  • heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen and sulfur.
  • heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen and sulfur.
  • Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.
  • heteroaryl used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refers to an optionally substituted group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, carbocyclic, or heterocyclic rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Non limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,
  • heteroaryl group may be mono- or bicyclic.
  • the term "heteroaryl" may be used
  • heteroaryl ring refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • Heterocyclic As used herein, the terms “heterocycle”, “heterocyclyl”,
  • heterocyclic radical and “heterocyclic ring” are used interchangeably and refer to a stable optionally substituted 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more heteroatoms, as defined above.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • Nitro refers to a group of the formula (-
  • Nitroso refers to a group of the formula
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • Unsaturated The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.
  • substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 y 2 R e , -(haloR*), -(CH 2 y 2 OH, -(CH 2 y 2 OR e , -(CH 2 y 2 CH(OR') 2 ; - 0(haloR e ), -CN, -N 3 , -(CH 2 y 2 C(0)R e , -(CH 2 y 2 C(0)OH, -(CH 2 y 2 C(0)OR e , -(CH 2 y 2 SR e , -(CH 2 y 2 SH, -(CH 2 y 2 NH 2 , -(CH 2 y 2 NHR e , -(CH 2 y 2 NR' 2 , -N0 2 , -SiR' 3 , -OSi
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR * 2 ) 2 _ 3 0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R include halogen, -R , -
  • each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0M heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , - S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C( H)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having C heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -
  • R -(haloR*), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or -N0 2 , wherein each R' is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0M heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the present invention provides, among other things, therapeutic compositions and methods that can effectively treat, slow or prevent mild cognitive impairment (MCI) or Alzheimer's disease (AD).
  • MCI mild cognitive impairment
  • AD Alzheimer's disease
  • the present invention is, in part, based on the following unexpected discoveries: (1) a protein complex PDS/TTR, known as a biomarker for early diagnosis of MCI or Alzheimer's disease, is neurotoxic and induces characteristic symptoms and features of Alzheimer's disease in cell cultures; (2)
  • dihydropyridine calcium channel blockers like nifedipine
  • their oxidized, nitroso derivatives and mixtures which no longer function as calcium channel blockers
  • T3/T4 effectively reduce or eliminate the ability of the PDS/TTR complex to induce AD-like symptoms and underlying enzymes and biochemical pathways in cell cultures and reduce endogenous levels of ⁇ 1-40 peptide in animal models
  • human association studies demonstrated that the use of dihydropyridine calcium channel blockers significantly delays the onset of cognitive decline thus indicating that these compounds may be used to effectively treat Alzheimer's disease.
  • nitroso nifedipine or a derivative thereof increases calcium influx.
  • the ability of these compounds to treat MCI or Alzheimer's disease may be independent of their ability to block calcium channels.
  • lactam such as NFD-
  • Ll can also effectively inhibit ⁇ 1-40 generation, reduce ⁇ processing enzymes and inactivate related biochemical pathways, both in vitro and in vivo, similar to nitroso- nifedipine.
  • nitroso- nifedipine may likely be a pro-drug that converts stoichiometrically into lactam once administered in vivo.
  • the present invention contemplates methods and compositions that can effectively treat Alzheimer's disease based on therapeutically effective amount of nifedipine, oxidized or nitroso nifedipine derivatives, lactam (e.g., a compound of formula (Ic) or (Ic-z), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof.
  • lactam e.g., a compound of formula (Ic) or (Ic-z), e.g., NFD-L1
  • T4 thyroxine
  • T3 triiodothyronine
  • the present invention provides methods for treating, slowing, or preventing Mild Cognitive Impairment (MCI) and/or Alzheimer's disease in a human subject, comprising administering to a subject who is suffering from or susceptible to MCI or Alzheimer's disease a therapeutically effective amount of an agent selected from the group consisting of nifedipine, oxidized nifedipine, nitroso-nifedipine, lactam (e.g., a compound of formula (Ic) or (Ic- ), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof, such that at least one symptom or feature associated with the MCI or Alzheimer's disease is reduced in abundance, intensity, severity, or frequency, or has delayed onset.
  • MCI Mild Cognitive Impairment
  • the present invention contemplates methods and compositions that can effectively treat Alzheimer's disease based on therapeutically effective amount of a compound of formula (la), (lb), (Ic), (II) and combinations thereof.
  • an agent suitable for the invention does not function as a calcium channel blocker.
  • an agent suitable for the invention increases calcium influx.
  • inventive methods according to the invention can be combined with sensitive biomarkers and/or cognitive test scores to identify patents, including those at an early stage of the disease, for treatment and to monitor efficacy of the treatment.
  • the present invention is particularly useful to treat early stage patients, especially, those patients having symptoms described as Mild Cognitive Impairment (MCI) and/or to prevent progression of MCI to Alzheimer's disease.
  • MCI Mild Cognitive Impairment
  • Therapeutic agents suitable for the present invention include both calcium channel blockers (e.g., dihydropyridine calcium channel blockers such as nifedipine) and non-calcium channel blockers (e.g., oxidized nifedipine, nitroso-nifedipine, mixture of nifedipine and its derivatives, thyroxine (T4), triiodothyronine (T3)).
  • calcium channel blockers e.g., dihydropyridine calcium channel blockers such as nifedipine
  • non-calcium channel blockers e.g., oxidized nifedipine, nitroso-nifedipine, mixture of nifedipine and its derivatives, thyroxine (T4), triiodothyronine (T3).
  • a therapeutic agent suitable for the present invention is of formula (la) or (lb):
  • R 1 and R 2 are independently Ci-6 aliphatic or cyano
  • R 3 and R 4 are independently C e aliphatic
  • R 5 is halogen, Ci_6 aliphatic, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, or nitroso;
  • n 0, 1, 2, or 3.
  • compounds of formula (la) are referred to as “reduced” or “dihydropyridines”.
  • compounds of formula (lb) are referred to as "oxidized” or “dehydro”.
  • R 1 and R 2 are independently C 1-3 alkyl. In some embodiments, R 3 and R 4 are independently C 1-4 alkyl. In some embodiments, R 1 and R 2 are methyl. In some embodiments, R 3 and R 4 are methyl.
  • a therapeutic agent suitable for the present invention is nifedipine, oxidized nifedipine, or nitroso-nifedipine.
  • nitroso-nifedipine is an oxidized analog of nifedipine, as shown below.
  • therapeutic agents suitable for the present invention include, but are not limited to, dihyropyridine compounds such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, manidipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.
  • dihyropyridine compounds such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, manidipine, lercanidipine, nicardipine,
  • therapeutic agents suitable for the present invention include, but are not limited to, oxidized amlodipine, oxidized aranidipine, oxidized azelnidipine, oxidized barnidipine, oxidized benidipine, oxidized cilnidipine, oxidized clevidipine, oxidized efonidipine, oxidized felodipine, oxidized isradipine, oxidized lacidipine, oxidized manidipine, oxidized lercanidipine, oxidized nicardipine, oxidized nifedipine, oxidized nilvadipine, oxidized nimodipine, oxidized nisoldipine, oxidized nitrendipine, and oxidized pranidipine.
  • an "oxidized" dihydropyridine compound e.g., oxidized amlodipine, oxidized nimodipine, oxidized nivaldipine
  • oxidized amlodipine, oxidized nimodipine, oxidized nivaldipine is the pyridine version of said compound.
  • nilvadipine oxidized nilvadipine [0129]
  • Further exemplary therapeutic agents include the following:
  • Z is H, F, CI, Br, or I.
  • a therapeutic agent suitable for the present invention is of formula (Ic):
  • R 1 and R 2 are independently an optionally substituted group selected from Ci_6 aliphatic, Ci-6 heteroaliphatic, aryl, heteroaryl, or cyano;
  • R 3 is an optionally substituted group selected from Ci_6 aliphatic, Ci_6 heteroaliphatic or aryl;
  • R 5 is halogen, optionally substituted Ci_6 aliphatic, optionally substituted Ci_6 heteroaliphatic, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, or nitroso;
  • n 0, 1, 2, or 3.
  • a therapeutic agent suitable for the present invention is of formula (Ic-z):
  • R 1 and R 2 are independently C e aliphatic or cyano
  • R 3 is Ci-6 aliphatic
  • R 5 is halogen, Ci_6 aliphatic, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, or nitroso;
  • n 0, 1, 2, or 3.
  • R 1 of formula (Ic) is an optionally substituted group selected from Ci_6 aliphatic, Ci_6 heteroaliphatic, aryl, heteroaryl, or cyano.
  • R 1 is substituted.
  • R 1 is unsubstituted.
  • R 1 is Ci_6 aliphatic.
  • R 1 is Ci_ 4 alkyl.
  • R 1 is methyl, ethyl, propyl, butyl, or isopropyl.
  • R 1 is methyl.
  • R 1 is isopropyl.
  • R 1 is cyano.
  • R 1 is Ci_6 heteroaliphatic.
  • R 1 is -OCH2CH2NH2.
  • R 1 is aryl.
  • R 1 is heteroaryl.
  • R 2 of formula (Ic) is an optionally substituted group selected from Ci_6 aliphatic, Ci_6 heteroaliphatic, aryl, heteroaryl, or cyano.
  • R 2 is substituted.
  • R 2 is unsubstituted.
  • R 2 is Ci_6 aliphatic.
  • R 2 is Ci_ 4 alkyl.
  • R 2 is methyl, ethyl, propyl, butyl, or isopropyl.
  • R 2 is methyl.
  • R 2 is isopropyl.
  • R 2 is cyano.
  • R 2 is Ci_6 heteroaliphatic.
  • R 2 is -OCH2CH2NH2.
  • R 2 is aryl.
  • R 2 is heteroaryl.
  • R 1 and R 2 are independently C 1-3 alkyl. In some embodiments, at least one of R 1 and R 2 is methyl. In some embodiments, R 1 and R 2 are methyl.
  • R 3 of formula (Ic) is an optionally substituted group selected from Ci_6 aliphatic, Ci_6 heteroaliphatic, or aryl.
  • R 1 is substituted.
  • R 1 is unsubstituted.
  • R 1 is Ci_6 aliphatic.
  • R 1 is C1-4 alkyl.
  • R 1 is methyl, ethyl, propyl, butyl, or isopropyl.
  • R 1 is methyl.
  • R 1 is isopropyl.
  • R 1 is ethyl.
  • R 1 is Ci_6
  • R 1 is -CH2CH2OCH3. In some embodiments, R 1 is aryl.
  • R 5 of formula (Ic) is halogen, optionally substituted Ci_6 aliphatic, optionally substituted Ci_6 heteroaliphatic, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro, or nitroso.
  • R 5 is substituted.
  • R 5 is unsubstituted.
  • R 5 is Ci_6 aliphatic.
  • R 5 is Ci- 4 alkyl.
  • R 5 is methyl, ethyl, propyl, butyl, or isopropyl.
  • R 5 is methyl.
  • R 5 is cyano.
  • R 5 is halogen. In some embodiments, R 5 is Ci-6 heteroaliphatic. In some embodiments, R 5 is hydroxyl. In some embodiments, R 5 is alkoxy. In some embodiments, R 5 is amino. In some embodiments, R 5 is alkylamino. In some embodiments, R 5 is nitro. In some embodiments, R 5 is nitroso.
  • n of formula (Ic) is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • a therapeutic agent suitable for the present invention is
  • a therapeutic agent suitable for the present invention is of formula (II):
  • X is -CH 2 - -0-, or -NH-;
  • Y is -H or -I.
  • X is -CH 2 - In some embodiments, X is -0-. In some embodiments, X is -NH-.
  • a therapeutic agent suitable for the present invention is thyroxine (T4) or triiodothyronine (T3):
  • T3 triiodothyronine
  • T4 thyroxine
  • a therapeutic agent suitable for the present invention is a mixture of various compounds described herein.
  • two or more compounds of formula (la) or (lb) can be combined to form a therapeutic agent.
  • two or more of nifedipine, oxidized nifedipine, and nitroso-nifedipine are combined.
  • T3 and/or T4 are combined with one or more of nifedipine, oxidized nifedipine, and nitroso-nifedipine.
  • nifedipine, oxidized nifedipine, and nitroso-nifedipine are combined to form a nifedipine mix or mixture.
  • a therapeutic agent according to the invention can be a mixture of two or more of nifedipine, oxidized nifedipine, nitroso-nifedipine, NFD-Ll, thyroxine (T4), and triiodothyronine (T3) at pre-determined mass or molar ratios.
  • a therapeutic agent suitable for the invention contains a mixture of nitroso-nifedipine and nifedipine.
  • nitroso-nifedipine and nifedipine can be mixed at a mass or molar ratio of about 1000: 1, about 500:1, about 200:1, about 100:1, about 64:1, about 32:1, about 16:1, about 10:1, about 8:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:8, about 1:10, about 1:16, about 1:32, about 1:64, about 1:100, about 1:200, about 1:500, or about 1:1000.
  • nitroso-nefidipine and nifedipine can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1:100 to about 1:10).
  • about 1:1000 to about 1000:1 e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100
  • a therapeutic agent suitable for the invention contains a mixture of oxidized-nifedipine and nifedipine.
  • oxidized-nifedipine and nifedipine can be mixed at a mass or molar ratio of about 1000:1, about 500:1, about 200:1, about 100:1, about 64:1, about 32:1, about 16:1, about 10:1, about 8:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:8, about 1:10, about 1:16, about 1:32, about 1:64, about 1:100, about 1:200, about 1:500, or about 1:1000.
  • oxidized-nefidipine and nifedipine can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1:100 to about 1:10).
  • about 1:1000 to about 1000:1 e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:
  • a therapeutic agent suitable for the invention contains a mixture of nitroso-nifedipine and oxidized nifedipine.
  • nitroso-nifedipine and oxidized-nifedipine can be mixed at a mass or molar ratio of about 1000:1, about 500:1, about 200:1, about 100:1, about 64:1, about 32:1, about 16:1, about 10:1, about 8:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:8, about 1:10, about 1:16, about 1:32, about 1:64, about 1:100, about 1:200, about 1:500, or about 1:1000.
  • nitroso-nefidipine and oxidized nifedipine can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1:100 to about 1:10).
  • about 1:1000 to about 1000:1 e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:
  • a therapeutic agent suitable for the invention contains a mixture of nitroso-nifedipine, oxidized nifedipine, and nifedipine.
  • nitroso-nifedipine, oxidized nifedipine, and nifedipine are mixed at a mass or molar ratio of about 5:1:3, 5:2:2, 6:3:1, 10:4:1, 3:1:5, 2:5:5, or 1:1:1.
  • a therapeutic agent contains a mixture of T3 and T4.
  • T3 and T4 can be mixed at a mass or molar ratio of about 1000:1, about 500:1, about 200:1, about 100:1, about 64:1, about 32:1, about 16:1, about 10:1, about 8:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:8, about 1:10, about 1:16, about 1:32, about 1:64, about 1:100, about 1:200, about 1:500, or about 1:1000.
  • T3 and T4 can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1:100 to about 1:10).
  • various compounds and mixtures described herein can be further combined to generate desirable therapeutic agents for the invention.
  • a T3/T4 mix can be combined with any of the nifedipine, nifedipine derivatives (e.g., oxidized or nitroso- nifedipine) or nifedipine mixtures described herein.
  • nifedipine nifedipine derivatives (e.g., oxidized or nitroso- nifedipine) or nifedipine mixtures described herein.
  • a therapeutic agent suitable for the invention comprises a mixture of nitroso-nifedipine and lactam (e.g., a compound of formula (Ic) or (lc-i) such as NFD-Ll).
  • nitroso-nifedipine and lactam e.g., a compound of formula (Ic) or (Ic-i) such as NFD-Ll
  • nitroso-nefidipine and lactam can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1:100 to about 1:10).
  • a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about
  • a therapeutic agent suitable for the invention contains a mixture of lactam (e.g., a compound of formula (Ic) or (Ic-/) such as NFD-Ll) and oxidized nifedipine.
  • lactam e.g., a compound of formula (Ic) or (Ic-i) such as NFD-Ll
  • oxidized-nifedipine can be mixed at a mass or molar ratio of about 1000:1, about 500:1, about 200:1, about 100:1, about 64:1, about 32:1, about 16:1, about 10:1, about8:l, about5:l, about 4:1, about3:l, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:8, about 1:10, about 1:16, about 1:32, about 1:64, about 1:100, about 1:200, about 1:500, or about 1:1000.
  • lactam e.g., a compound of formula (Ic) or (Ic-) such as NFD-Ll
  • oxidized nifedipine can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1 : 100 to about 1 : 10).
  • a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to
  • a therapeutic agent suitable for the invention contains a mixture of lactam (e.g., a compound of formula (Ic) or (Ic-i) such as NFD-Ll), oxidized nifedipine, and nifedipine.
  • lactam e.g., a compound of formula (Ic) or (Ic-i) such as NFD-Ll
  • oxidized nifedipine, and nifedipine are mixed at a mass or molar ratio of about 5:1:3, 5:2:2, 6:3:1, 10:4:1, 3:1:5, 2:5:5, or 1:1:1.
  • a therapeutic agent contains a mixture of T3 and T4.
  • T3 and T4 can be mixed at a mass or molar ratio of about 1000: 1, about 500: 1, about 200: 1, about 100:1, about 64:1, about 32:1, about 16:1, about 10:1, about 8:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:8, about 1:10, about 1:16, about 1:32, about 1:64, about 1:100, about 1:200, about 1:500, or about 1 : 1000.
  • T3 and T4 can be mixed at a mass or molar ratio ranging from about 1:1000 to about 1000:1 (e.g., about 1:500 to about 500:1, about 1:200 to about 200:1, about 1:100 to about 100:1, about 1:10 to about 10:1, about 1:16 to about 16:1, about 1:32 to about 32:1, about 1:64 to about 64:1, about 1:1 to about 32:1, about 1:1 to about 10:1, about 100:1 to about 1000:1, about 10:1 to about 100:1, about 1:1000 to 1:1, about 1:1 to about 1000:1, or about 1:100 to about 1:10).
  • various compounds and mixtures described herein can be further combined to generate desirable therapeutic agents for the invention.
  • a T3/T4 mix can be combined with any of the nifedipine, nifedipine derivatives (e.g., oxidized or nitroso-nifedipine), compound of formula (I-c) (e.g., NFD-Ll, or nifedipine mixtures described herein.
  • biomarkers can be used to identify subject or patient who is suffering from, susceptible to or at risk of MCI or Alzheimer's disease.
  • a biomarker is a characteristic bio-molecule which is differentially present in a sample taken from a subject of one phenotypic status (e.g., having a disease) as compared with another phenotypic status (e.g., not having a disease).
  • a biomarker is differentially present between different phenotypic statuses if the mean or median expression level of the biomarker in the different groups is calculated to be statistically significant.
  • Biomarkers, alone or in combination provide measures of relative risk that a subject belongs to one phenotypic status or another. Therefore, they are useful as markers for disease (diagnostics), therapeutic effectiveness of a drug (theranostics) and drug toxicity.
  • levels of a ⁇ 55 kDa proteinaceous complex containing prostaglandin-D2-synthase and transthyretin may serve as a sensitive and specific diagnostic biomarker of MCI and AD, as detailed in US Pat. Pub. No. 2008/0026405, which is incorporated herein by reference.
  • the PDS/TTR complex presents in cerebrospinal fluid and appears to be a sensitive and specific biomarker of the disease. Formation of the PDS/TTR complex was been localized to the choroid plexus, an assembly of epithelial cells located adjacent to the lateral ventricles. The choroid plexus functions as the blood-CSF barrier. The choroid plexus passes water, salts and selected small molecules from the blood to the CSF but effectively prevents blood proteins form entering the CSF. Proteins required for CSF are synthesized by the choroid plexus. Thus, the choroid plexus also functions as the source of CSF.
  • Epithelial cells isolated from choroid plexus obtained fresh from short post mortem autopsies of late stage AD patients have been grown and expanded in culture. Examination of cell culture medium obtained from AD epithelial cells showed elevated levels of the PDS/TTR complex compared to control cells. Thus, an elevated PDS/TTR complex level as compared to a normal control can be used to identify subjects or patients suffering from, susceptible to or at risk of developing MCI or Alzheimer's disease.
  • a biomarker suitable for the present invention comprises at least one of transthyretin and/or a prostaglandin-H2 D-isomerase, and at least one second protein selected from tranthyretin, prostaglandin-H2 D-isomerase, beta-2- microglobulin, cystatin C, superoxide dismutase [Cu-Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2 and/or serotransferrin. Mild cognitive impairment or Alzheimer's disease status is determined by correlating the obtained measurement with standards.
  • neuronal thread protein, tau (total; T-tau and various phosphorylated forms; P-tau), and/or derivatives of amyloid precursor protein (APP) including ⁇ 40 and ⁇ 42 may be used as biomarkers to identify patient population for treatment with compositions and methods of the present invention.
  • a subject in need of treatment has an abnormal level of a protein biomarker complex as compared to a control, wherein the protein biomarker complex comprises one or more of (i) beta amyloid 40 ( ⁇ 40), (ii) beta amyloid 42 ( ⁇ 42), (iii) the ratio of ⁇ 40 to ⁇ 42, and (iv) the ratio of phosphorylated tau to total tau.
  • a biomarker is determined in a fluid sample obtained from the subject.
  • a fluid sample is selected from the group consisting of CSF, serum, whole blood, blood plasma, urine, ascitic fluid, saliva, tissue effusion, lavage, and combinations thereof.
  • ELISA sandwich enzyme linked immunoassay
  • the measured level of a biomarker is compared to one or more controls or reference levels.
  • Suitable reference level used for comparison with the measured level for a AD biomarker may vary, depending on aspect of the invention being practiced, as will be understood by one of ordinary skill in the art.
  • a suitable "reference level” is typically a level indicative of healthy individuals, in particular, age-matched healthy individuals.
  • a reference level can be determined in parallel with patient sample.
  • a reference level can also be a pre-determined level or based on historical data.
  • a suitable reference level can be an average of levels obtained from a population that is not afflicted with AD or MCI.
  • a suitable reference level is derived from (e.g., is the mean or median of) levels obtained from an age- matched population.
  • a subject in need of treatment has an greater or elevated level of a biomarker described herein as compared to a control or reference level indicative of a healthy individual or population.
  • a suitable reference level is typically a level indicative of healthy individuals or individuals suffering from Alzheimer's disease (e.g., with a pre-determined stage, such as MCI, EAD, or LAD).
  • a reference level can be determined in parallel with patient sample.
  • a reference level can also be a pre-determined level or based on historical data.
  • a suitable reference level can be an average of levels obtained from a population that is not afflicted with AD or MCI, or a population that has been diagnosed with MCI or AD (e.g., EAD or LAD).
  • a suitable reference level may be a historical reference level for a particular patient, for example, a level that was obtained from a sample derived from the same individual, but at an earlier point in time (e.g., before the treatment or an earlier point in the treatment).
  • a suitable reference level is derived from (e.g., is the mean or median of) levels obtained from an age-matched population.
  • suitable reference levels are normally derived from (e.g., is the mean or median of) levels obtained from a population which has been diagnosed with a particular stage of AD (e.g., EAD or LAD) or MCI.
  • the level of a suitable biomarker (such as the ⁇ 55 kDa
  • PDS/TTR complex can be used to monitor the efficacy of the treatment.
  • the goal of a therapy would be, ideally, to decrease, lower or diminish the level of the PDS/TTR complex in a subject so that a fluid sample taken from the subject would contain no detectable complex.
  • a more conservative, subsidiary, goal of therapy would be to forestall any increase in the level of the ⁇ 55 kDa PDS/TTR complex.
  • a person of ordinary skill in the medical therapeutic arts would be able to determine whether a given therapeutic regime is accomplishing the chosen therapeutic goal based on the level of an appropriate biomarker. In this way, a person of ordinary skill in the medical therapeutic arts would also be able to determine the effective amount of a therapeutic agent described herein based on the measured level of a suitable biomarker as compared to appropriate controls or reference levels.
  • aged-matched populations are used to derive various reference levels.
  • Age-matched populations are ideally the same age as the individual being tested, but approximately age-matched populations are also acceptable.
  • Approximately age-matched populations may be within 1, 2, 3, 4, or 5 years of the age of the individual tested, or may be groups of different ages which encompass the age of the individual being tested.
  • Approximately age-matched populations may be in 2, 3, 4, 5, 6, 7, 8, 9, or 10 year increments (e.g. a "5 year increment" group which serves as the source for reference values for a 62 year old individual might include 58-62 year old individuals, 59-63 year old individuals, 60-64 year old individuals, 61-65 year old individuals, or 62-66 year old individuals).
  • a "5 year increment" group which serves as the source for reference values for a 62 year old individual might include 58-62 year old individuals, 59-63 year old individuals, 60-64 year old individuals, 61-65 year old individuals, or 62-66 year old individuals).
  • the process of comparing a measured value and a reference value can be carried out in any convenient manner appropriate to the type of measured value and reference value for the AD biomarker at issue.
  • “measuring” can be performed using quantitative or qualitative measurement techniques, and the mode of comparing a measured value and a reference value can vary depending on the measurement technology employed.
  • the measured values used in the methods of the invention will most commonly be quantitative values (e.g., quantitative measurements of concentration, such as nanograms of AD biomarker per milliliter of sample, or absolute amount).
  • the comparison can be made by inspecting the numerical data, by inspecting representations of the data (e.g., inspecting graphical representations such as bar or line graphs).
  • a measured value is generally considered to be substantially equal to or greater than a reference value if it is at least about 95% of the value of the reference value (e.g., a measured value of 1.71 can be considered substantially equal to a reference value of 1.80).
  • a measured value is considered less or lower than a reference value if the measured value is less than 95% of the reference value (e.g., a measured value of 1.7 can be considered less than a reference value of 1.80).
  • MMSE Mini Mental Status Examination
  • CDR Clinical Dementia Rating
  • an MMSE score is used to identify a subject in need of treatment with the compositions and methods described herein.
  • An MMSE score is a composite score representing multiple tests of cognitive function. The maximum possible total MMSE score is 30 points. The MMSE can be used to classify the severity of cognitive impairment in patients with dementia or other medical conditions. Table 1 shows how MMSE scores generally represent degrees of cognitive function.
  • a subject in need of treatment has an MMSE score of
  • a CDR score is used to identify a subject in need of treatment with the compositions and methods described herein.
  • An CDR score is constructed from six domains that are scored individually: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Table 2 shows how CDR scores generally represent degrees of cognitive function.
  • a CDR score above 0 indicates that a subject may be suffering from, susceptible to or at risk of MCI or Alzheimer's disease.
  • a subject in need of treatment may have a CDR score of 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate dementia), or 3 (severe dementia).
  • a cognitive test score (such as an MMSE score or CDR score) can be used to monitor the efficacy of the treatment.
  • an effective therapy should improve the cognitive test score. Therefore, by comparing the cognitive test scores before and after the treatment or from different time points of a treatment regimen, a person of ordinary skill in the medical therapeutic arts can determine whether a given therapeutic regime is effective. For example, a person of ordinary skill in the medical therapeutic arts would be able to determine or adjust the effective amount of a therapeutic agent described herein by based on relative cognitive test scores determined before the treatment or from different time points of a treatment regimen.
  • the present invention encompasses pharmaceutical compositions comprising therapeutic agents such as those disclosed herein.
  • a pharmaceutical composition of the invention contain a therapeutically effective amount of a therapeutic agent and a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable carrier” means a nontoxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline, Ringer's solution; ethyl
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • antioxidants examples include, but are not limited to, water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT
  • terapéuticaally effective amount refers to an amount of therapeutic agent that is sufficient, when administered to a subject in need of treatment according to an appropriate regimen, to alleviate, ameliorate, stabilize, and/or delay the onset of at least one symptom or feature associated with MCI or Alzheimer's disease as well as delay in progression of one or more symptoms of MCI or Alzheimer's disease (e.g., delay in progression with respect to abundance, intensity, severity, or frequency). It will be understood, however, that the total daily usage of the therapeutic agents and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coinciding with the specific compound employed; and like factors well known in the medical arts.
  • a therapeutically effective dose of a therapeutic agent of the present invention can range, for example, from 0.01 to 100 mg/kg body weight or more. In some embodiments, a therapeutically effective dose of a therapeutic agent of the present invention ranges from about 0.1 to about 50 mg/kg body weight (e.g., about 0.1 to about 35 mg/kg, about 0.1 to about 15 mg/kg, about 6.25 to about 35 mg/kg, about 12.5 to about 35 mg/kg, about 6.25 to about 25 mg/kg, about 35 mg/kg).
  • a therapeutically effective amount of a therapeutic agent ranges from about 0.01 mg to about 2.5 g per dose (e.g., from about 0.01 mg to about 2.0 g, from about 0.01 mg to about 1.5 g, from about 0.01 mg to about 1.0 g, per dose).
  • a therapeutically effective amount of a therapeutic agent ranges from about 0.01 to about 1000 mg (e.g., about 0.01 to about 500 mg, about 0.01 to about 250 mg, about 0.01 to about 200 mg, about 0.01 to about 150 mg, about 0.01 to about 100 mg, about 0.01 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.5 mg, about 0.01 to about 0.1 mg) per dose.
  • about 0.01 to about 1000 mg e.g., about 0.01 to about 500 mg, about 0.01 to about 250 mg, about 0.01 to about 200 mg, about 0.01 to about 150 mg, about 0.01 to about 100 mg, about 0.01 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about
  • the therapeutically effective amount of a therapeutic agent ranges from about 100 mg to about 5 g (e.g., about 100 mg to about 3 g, about 100 mg to about 2.5 g, about 100 mg to about 2 g, about 100 mg to about 1.5 g, about 100 mg to about 1000 mg, about 100 mg to about 500 mg, about 100 mg to about 250 mg) per dose.
  • a therapeutically effective amount of a therapeutic agent can be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 500 mg, about 1000 mg, about 1.5 g, about 2 g, about 2.5 g, about 3 g, or about 5 g per dose.
  • the amount described herein is the total amount of all active compounds in a composition.
  • a therapeutically effective amount is the combined amount of nifedipine, nitroso-nifedipine and oxidized nifedipine.
  • a therapeutically effective amount of a therapeutic agent as described herein is an amount insufficient to induce an adverse event (e.g., liver toxicity) in a human subject.
  • a therapeutic agent as described herein is administered once daily. In some embodiments, a therapeutic agent as described herein is administered multiple times per day, e.g., twice, three times, or four times daily. In some embodiments, a total daily dose of a therapeutic agent ranges from about 0.01 mg to about 5 g per day in multiple doses or in a single dose (e.g., from about 0.01 mg to about 4.0 g, from about 0.01 mg to about 3.0 g, from about 0.01 mg to about 2.5 g, from about 0.01 mg to about 2.0 g, from about 0.01 mg to about 1.5 g, from about 0.01 mg to about 1.0 g, per day in multiple doses or in a single dose).
  • a total daily dose of a therapeutic agent ranges from about 0.01 to about 1000 mg (e.g., about 0.01 to about 500 mg, about 0.01 to about 250 mg, about 0.01 to about 200 mg, about 0.01 to about 150 mg, about 0.01 to about 100 mg, about 0.01 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about 1.5 mg, about 0.01 to about 1.0 mg, about 0.01 to about 0.5 mg, about 0.01 to about 0.1 mg) per day in a single dose or in multiple doses.
  • about 0.01 to about 1000 mg e.g., about 0.01 to about 500 mg, about 0.01 to about 250 mg, about 0.01 to about 200 mg, about 0.01 to about 150 mg, about 0.01 to about 100 mg, about 0.01 to about 50 mg, about 0.01 to about 10 mg, about 0.01 to about 5 mg, about 0.01 to about 2.5 mg, about 0.01 to about 2.0 mg, about 0.01 to about
  • a total daily dose of a therapeutic agent ranges from about 50 mg to about 5 g (e.g., about 50 mg to about 4 g, about 100 mg to about 3 g, about 100 mg to about 2.5 g, about 100 mg to about 2 g, about 100 mg to about 1.5 g, about 100 mg to about 1000 mg, about 100 mg to about 500 mg, about 100 mg to about 250 mg) per day in a single dose or in multiple doses.
  • a therapeutic agent in particular, nitroso-nifedipine
  • a total daily dose of a therapeutic agent can be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 500 mg, about 1000 mg, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, or about 5 g.
  • an amount described herein is the total amount of all active compounds in a composition.
  • a therapeutically effective amount is the combined amount of nifedipine, nitroso-nifedipine and oxidized nifedipine.
  • a therapeutic agent as described herein is administered monthly, bi-weekly, weekly, twice a week, or three times a week.
  • the daily doses described above reflects the average daily dose.
  • the active agent in certain situations, it may be important to maintain a fairly high dose of the active agent in the blood stream of the patient, particularly early in the treatment. Hence, at least initially, it may be important to keep the dose relatively high and/or at a substantially constant level for a given period of time, e.g., at least about six or more hours, e.g., at least about twelve or more hour, e.g., at least about twenty-four or more hours.
  • the compounds of the present invention may be administered alone or in combination or in concurrent therapy with other agents which affect the central or peripheral nervous system, particularly selected areas of the brain.
  • compositions according to the present invention may be administered by any route, including oral, subcutaneous, intravenous, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, rectal, auricular, conjunctival, cutaneous, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra-articular, intrabiliary, introbrochial, intrabursal, intracardiac, intracaritlaginous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, intracoronary, intracorporus cavernosum, intradermal, intradiscal, intraductal, intraduodenal, intrad
  • a pharmaceutical composition of the present invention is administered by a route selected from oral, subcutaneous, intravenous, transdermal, intraperitoneal, intramuscular, intracerebroventricular, intraparenchymal, intrathecal, intracranial, buccal, mucosal, nasal, and rectal. In certain embodiments, a pharmaceutical composition of the present invention is administered orally.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water, isotonic solutions, or saline.
  • Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; sweetening, flavoring and perfuming agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility.
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drug, which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying absorption of a drug is to administer the drug as a solution or suspension in oil.
  • Injectable depot forms can also be made by forming microcapsule matrices of drugs and biodegradable polymers, such as polylactide-polyglycoside.
  • the rate of drug release can be controlled.
  • biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectables can also be made by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
  • a suitable non-irritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, gelcaps and granules.
  • therapeutic agent may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • dosage forms may also comprise additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and
  • microcrystalline cellulose in the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release-controlling coatings.
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons.
  • Transdermal patches can provide controlled delivery of active compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions described herein can be formulated for immediate release or controlled release (also referred to as slow, sustained or extended release).
  • immediate release or controlled release also referred to as slow, sustained or extended release
  • Various slow or extended release formulations or devices are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 5,674,533, 5,059,595, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example,
  • hydropropylmethyl cellulose other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- release formulations known to those of ordinary skill in the art can be readily selected and adapted for use with therapeutic agents of the invention.
  • the invention encompasses solid oral dosage forms such as, but not limited to, tablets, capsules, gelcaps, and caplets that are formulated for controlled-release (i.e., slow release, extended release, or sustained release).
  • controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled or extended release formulations can keep adequate dose levels constantly available inside a patient body to enhance delivery across the blood-brain barrier.
  • Controlled-release formulations are designed to initially release an amount of therapeutic agent (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of thug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the drug In order to maintain this constant level of drug inside the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • two or more therapeutic agents may be administered in combination.
  • the two or more therapeutic agents may be administered separately from one another, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two therapeutic agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the invention is provided in numerous embodiments and can be discerned, inter alia, in various examples.
  • the following examples provide an illustrative but non- limiting description of the breadth and applicability of the invention.
  • acrolein an alpha, beta unsaturated three carbon aldehydic by-product of lipid peroxidation
  • acrolein causes normal control epithelial cells to express the PDS/TTR complex into culture medium at comparable levels to the epithelial cells derived from Alzheimer's disease patients.
  • primary cultures of choroid plexus epithelail cells were established from short post mortem interval autopsies using established methods. AD and normal control cultures were grown to confluence in MEM growth medium containing 2% fetal bovine serum and 1% epithelial growth factor (EGF).
  • EGF epithelial growth factor
  • FIG. 1 shows exemplary results illustrating an Western blot analysis of the PDS/TTR complex expressed in cell culture medium by control epithelial cells, control epithelial cells treated with acrolein, and epithelial cells derived from late stage Alzheimer's disease patients.
  • acrolein increased the expression of the PDS/TTR complex in control epithelial cells to a level comparable to that in late stage AD (LAD) epithelial cells.
  • SY5Y neuroblastoma cells were exposed to conditioned medium from LAD or normal control epithelial cells for 16 hours. Following exposure to conditioned medium, cells were fixed in 70% methanol/30% acetone and were subjected to immunohistochemistry using anti-PHF-1 antibody. PHF- 1 recognizes aberrantly phosphorylated Tau as observed in AD NFT
  • results of the assays showed the PDS/TTR complex activated 2 inflammatory cytokine pathways (i.e., IL-6, TNF-a) in astrocytoma cultures (data not shown), indicating a role of the PDS/TTR in neuroinflammation.
  • IL-6 inflammatory cytokine pathways
  • PDS/TTR complex causes various biochemical changes that can directly impact hallmarks of Alzheimer's disease.
  • Example 1 The assays described in Example 1 provide a tool to identify potential therapeutic agents that can protect neuronal cells against the PDS/TTR complex.
  • compounds such as nifedipine (l,4-dihydro-2,6-dimethyl-4-(2- nitrophenyl)-3,5-pyridinydicarboxylic acid dimethyl ester, CAS#21829-25-4 (Sigma Aldrich)), a calcium channel blocker prescribed for high blood pressure; or nifedipine analogs such as oxidized derivative of nifedipine ((2,6-dimethyl-4-(2-nitrophenyl)- 3,5- pyridinedicarboxylic acid dimethyl ester, CAS# 67035-22-7 (Sigma Aldrich)) or a nitroso derivative of nifedipine (2,6-dimethyl-4-(2-nitrosophenyl)- 3,5-pyridinedicarboxylic acid dimethyl ester, CAS#50428-14-3 (S
  • epithelial cells were treated with 5 ⁇ acrolein, 5 ⁇ acrolein plus 0.5 ⁇ T3/ 0.5 ⁇ T4, 5 ⁇ acrolein plus 1 ⁇ nifedipine mixture (nitroso-nifedipine 55%, oxidized nifedipine 1 1% and nifedipine 34%), or 5 ⁇ acrolein plus 1 ⁇ nifedipine mixture and 0.5 ⁇ T3/ 0.5 ⁇ T4, as described in Example 1.
  • the amount of PDS/TTR secreted into the culture medium by each culture was determined by Western blot analysis as described above. Exemplary data was shown in Figure 4.
  • Nifedipine analogs inhibit inflammatory cytokine production [0207] It was reported that inflammatory response elements (cytokines) are elevated in Alzheimer's disease patients. The inventors tested the nifedipine mix and individual analogs in astrocytoma cultures. Human astrocytoama cells were plated at 2.5 X 10 5 cells/well in 6 well culture plates and were grown for 24 hours. Cultures were then switched to serum free Opti-MEM and treated with the nifedipine mixture and individual analogs for 24 hours. Three 6-well plates were subjected to each treatment. Following treatment, medium was collected from each well and levels of IL-1B, IL-6, TNF-a and TGF-B were measured using commercially available ELISAs.
  • FIG. 7 Exemplary results are shown in Figure 7. As can be seen from Figure 7, IL-1, IL-6 and TNF-a secreted in the medium were significantly reduced with the treatment of nifedipine mix or oxidized nifedipine, indicating these compounds have a direct positive effect on neuroinflammation.
  • NFD-L1 was tested in astrocytoma cultures. As can be seen from Figure 8, IL-1, IL-6, and TNF-a secreted in the medium were significantly reduced with the treatment of NFD-L1, indicating that NFD-L1 has a direct positive effect on neuroinflammation. The results shown in this example indicate that a lactam such as NFD-L1 can effectively inhibit inflammatory condition in the central nervous system.
  • SY5Y neuroblastoma cells exposed to medium from LAD epithelial cells that contained significantly higher levels of the PDS/TTR complex displayed significantly increased PHF-1 immunostaining as compared to those exposed to medium from untreated control cultures.
  • SY5Y cells were exposed to medium from epithelial cells treated with acrolein and combinations of nifedipine, nifedipine analogs, mixtures of nifedipine analogs and T3/T4 using procedures described in Example 1.
  • nifedipine mix and nifedipine/nifedipine analogs plus T3/T4 significantly reduced PHF-1 levels.
  • Example 6 Inhibition of ⁇ 1-42 production from H4 neuroglioblastoma cells
  • H4 neuroglioblastoma cells stably transfected to overexpress amyloid precursor protein (APP) to further investigate if nifedipine, nifedipine analogs (e.g., oxidized nifedipine or nitroso-nifedipine) and/or T3/T4 can inhibit the production of ⁇ 1-42.
  • H4 neuroglioblastoma cells stably transfected with a construct overexpressing amyloid precursor protein (APP) secret ABi_ 42 into the culture medium.
  • H4 cells were treated with 1 ⁇ fresh nifedipine, 1 ⁇ oxidized nifedipine, 1 ⁇ nitroso-nifedipine, or 0.5 ⁇ T3/0.5 ⁇ T4 for 16 hours.
  • the AB levels in the culture medium were measured using ELISAs (Invitrogen). As shown in Figure 10, treatment of fresh nifedipine, oxidized nifedipine, nitroso-nifedipine, or T3/T4 lead to significantly decreased production of AB 1-42.
  • T3/T4 improves the inhibitory effect of nifedipine, nifedipine analogs and nifedipine mix on AB1-42 production.
  • NFD-L1 was tested for inhibition of ⁇ 1-42 generation in H4 neuroglioma cultures. As shown in Figure 13, ⁇ 1-42 generation is inhibited by NFD-L1. The results shown in this example indicate that a lactam such as NFD-L1 can effectively inhibit ⁇ 1-42 production.
  • ⁇ _ 42 production depends on the activity of beta secretase (BACE), an enzyme that cleaves the amyloid precursor protein at the beta secretase cleavage site, and the gamma secretase complex composed of presenilin-1 (PS-1), nicastrin, APH-1 and PEN-2 that cleaves at the gamma secretase cleavage site.
  • BACE beta secretase
  • PS-1 presenilin-1
  • PS-1 presenilin-1
  • APH-1 and PEN-2 cleaves at the gamma secretase cleavage site.
  • BACE activity was measured using a fluorescent substrate and purified recombinant BACE as part of a commercial kit from Invitrogen. As shown in Figure 14, nifedipine alone or in combination with thyroxine slightly inhibited BACE activity; however, nitroso-nifedipine alone and in combination with thyroxine led to significant inhibition of BACE activity (Figure 14).
  • NFD-Ll was tested for inhibition of BACE activity. As shown in Figure 15, NFD-Ll inhibits BACE. This example indicates that a lactam such as NFD-Ll can effectively inhibit beta secretase (BACE) activity.
  • BACE beta secretase
  • C57BL/6 mice were subjected to intraperitoneal (IP) injections of vehicle (2%DMSO/98% polyethylene glycol-3000 (PEG-3000), 25 mg/kg nifedipine or nifedipine mix, T3/T4 (10 mg/kg T3 and 10 mg/kg T4), nifedipine mix plus T3/T4 and nifedipine plus T3/T4 on three consecutive days. Animals were euthanatized 1 hour after the third injection. The brains and terminal serum were removed and immediately frozen in liquid nitrogen and stored at -80 °C until used for analysis.
  • vehicle 2%DMSO/98% polyethylene glycol-3000 (PEG-3000)
  • T3/T4 10 mg/kg T3 and 10 mg/kg T4
  • T3/T4 10 mg/kg T3 and 10 mg/kg T4
  • mice treated with both T3/T4 and nifedipine mix plus T3/T4 showed a modest (25%) but significant decrease in ⁇ ! _ 40 levels compared to animals treated with vehicle.
  • levels of PS-1, Nicast, and APH-1 were significantly decreased in mice treated with nifedipine, nifedipine mix plus T3/T4.
  • BACE protein levels were significantly decreased in mice treated with nifedipine, nifedipine plus T3/T4 and T3/T4 alone. In contrast, there were no significant differences in levels of cleaved Notch with any treatment ( Figure 17).
  • nifedipine was found in all samples analyzed indicating that components of the mixture were passing the blood-brain barrier and thus available for neuronal protection. This experiments has shown that these derivatives possess the brain permeability desired for treatment of Alzheimer's disease.
  • Example 1 Nitroso-nifedipine inhibits production of Afil-40 in vivo
  • T3/T4 can inhibit the orphan G-coupled receptor protein 3 (GPCR-3), an enzyme which is suggested to play a role in maintaining stability of the gamma secretase complex (which, as discussed above, is important for cleavage of APP to form ⁇ ).
  • GPCR-3 G-coupled receptor protein 3
  • H4 neuroglioblastoma cells were treated with 1 ⁇ mixed nifedipine, 1 ⁇ mixed nifedipine plus 0.5 ⁇ T3/0.5 ⁇ T4, 0.5 ⁇ ⁇ 3/0.5 ⁇ ⁇ 4, 1 ⁇ fresh nifedipine, 1 ⁇ fresh nifedipine plus 0.5 ⁇ T3/0.5 ⁇ ⁇ 4 for 16 hours.
  • Levels of GPCR-3 were measured using Western blot analysis using a GPCR-3 specific antibody. As shown in Figure 19, nifedipine mixtures, fresh nifedipine, and/or T3/T4 significantly reduced GPCR-3 expression levels in H4 cells.
  • GPCR-3 levels were determined in the C57BL/6 mice described above in Example 10 using Western blot analysis. Exemplary results are also shown in Figure 19. Nifedipine mixtures and T3/T4, fresh nifedipine, and T3/T4 also reduced GPCR-3 expression levels in mice.
  • nitroso-nifedipine was first determined based on the survival rate of H4 cells treated with increasing concentrations of nitroso-nifedipine. Specifically, H4 neuroglioma cultures were plated at a density of 2.5 X 10 5 cells/well and allowed to attach overnight. Cultures were switched to Opti-MEM and treated for 16 hours with increasing concentrations of nitroso-nifedipine. Following treatment, MTT was added at a final concentration of 0.5 mg/mL and cultures incubated for 30 minutes.
  • H4 neuroglioma cultures that overexpress APP were plated at a density of 2.5 X 10 5 cells/dish and allowed to attach overnight. Cultures were switched to Opti-MEM and treated with 2.5 ⁇ or 0.5 ⁇ nitroso-nifedipine alone or 2.5 ⁇ nitroso-nifedipine + nifedipine (0.1 and 0.01 ⁇ ) or 1 ⁇ T3/T4. Following treatment, cultures were rinsed three times in PBS and fixed in 70% methanol/30% acetone for 30 minutes at -20 °C.
  • NFD-Ll Using a similar procedure as described in Example 13, H4 neuroglioma cultures were treated with NFD-Ll to determine the effects of NFD-Ll on levels of enzymes involved in AB processing. As shown in Figure 23, similar to nitroso-nifedipine, NFD-Ll led to a significant decrease in BACE protein and a significant increase in ADAM-10. NFD-Ll also led to a significant decrease in PS-1 and NCT. This example demonstrated that treatment with lactam such as NFD-Ll has significant effect on levels of enzymes involved in AB processing.
  • Example 15 Effects of nitroso-nifedipine on levels of enzymes involved in AB processing in vivo
  • ADAM-10 which functions as an alpha secretase. It is contemplated that increased ADAM-10 levels lead to increased cleavage at the alpha secretase position of APP, minimizing generation of AB.
  • NFD-Ll The effects of NFD-Ll on levels of enzymes involved in AB processing in vivo were determined using a similar procedure to that described in Example 15. As shown in Figure 25, similar to nitroso-nifedipine, IP injections of NFD-Ll led to a significant decrease in AB1-40 and a significant decrease in presenilin- 1. The data also show that NFD- Ll mediated inhibition of PS-1 led to a significant increase in levels of cleaved Notch-1. In addition, treatment with NFD-Ll led to a significant increase in levels of ADAM-10. Thus, this example demonstrated that treatment with lactam such as NFD-L1 has significant effect on levels of enzymes involved in AB processing in vivo.
  • nifedipine, nifedipine mixtures, their oxidized and nitroso derivatives, and/or T3/T4 can reduce phosphorylated Tau protein.
  • Phosphorylated tau protein can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease.
  • GSK-3 glycogen synthase kinase-3B
  • Akt protein kinase B
  • Akt a serine/threonine kinase is regulated by phosphatidy linos itol kinase (PI3K) mediated signaling and is activated by phosphorylation of a regulatory threonine residue (Thr-308) by phosphatidylinositol dependent kinase 1 (PDK1) and by phosphorylation of Ser 473 by PDKa/TORC2 kinase.
  • PI3K phosphatidy linos itol kinase
  • PDK1 phosphatidylinositol dependent kinase 1
  • Akt/GSK-3 pathway may be mediated by GCPRs coupled to G a i2/i3 heterotrimeric G proteins.
  • Activation of Gai2 has been shown to stimulate RhoA and its effector Rho kinase (ROCK).
  • ROCK phosphorylated at serl60 further trans activates a receptor tyrosine kinase (RTK) that activates the PI3K signaling pathway leading to phosphorylation/activation of Akt/GSK-3 (reviewed by New et al, "G protein-coupled receptor-induced Akt activity in cellular proliferation and apoptosis," FEBS J, 2007; 274:6025-36.).
  • RTK receptor tyrosine kinase
  • Phosphoryalted Akt increases phosphorylation and inactivation of GSK-3 therefore reducing Tau phosphorylation.
  • Example 18 Effects of nifedipine and nitroso-nifedipine on glutamate transport
  • tissue specimens from C57/B16 mice treated acutely for 3 days with 25 mg/kg nifedipine we subjected 20 ⁇ g samples of protein to Western blot analysis and probed for EAAT2. Results of the analysis showed a significant increase in EAAT2 with nifedipine. Together, these data suggest that both nifedipine and nitroso-nifedipine lead to increased levels of a key glutamate transporter shown to be altered in AD brain.
  • dihydropyridine calcium channel blockers appears to delay the onset of cognitive decline, suggesting dihydropyridine calcium channel blockers can be used to treat neurodegenerative diseases such as Alzheimer's disease.
  • ⁇ 1-42 and ⁇ processing enzymes such as PS-1, Nicas, BACE, APH-1 and PEN-2 in front lobe specimens of subjects were determined using standard methods. Specifically, ⁇ 1-42 levels were determined using Invitrogen ELISAs and protein levels were determined using Western blot analysis and antibodies specific to each protein. As shown in Figure 30, the ⁇ 1-42 level was significantly reduced in subjects with drugs as compared to that in subjects without drugs. Some ⁇ processing enzymes including PS-1, Nicas were significantly reduced in those subjects with drugs as compared to those without drugs. Interestingly, the levels of BACE, APH-1 and PEN-2 were increased in those subjects with drugs as compared to subjects without drugs.
  • nitroso-nifedipine does not function as a calcium channel blocker. Surprisingly, nitroso-nifedipine increases calcium influx. Without wishing to be bound by any theory, it is contemplated that nitroso-nifedipine and its derivatives treat MCI or Alzheimer's disease through a novel mechanism independent of blocking calcium channels.
  • Example 22 Synthesis of nitroso-nifedipine
  • nitrosonifedipine Specifically, nifedipine (20 mg) was dissolved in 10 mL acetonitrile in a pyrex culture tube, capped and photolyzed with a 250W halogen lamp (3M EVW) for 30 minutes. The product was isolated by solvent removal on a rotary evaporator to obtain a blue-green oil (18.1 mg, 94% yield). GC/MS analysis showed greater than 98.5% conversion to nitrosonifedipine. An exemplary result is shown in Figure 33.
  • NFD-L1 Nitroso-nifedipine (10 mg, 30.5 ⁇ ) dissolved in 5 mL ethanol was mixed with glutathione (93 mg, 305 ⁇ ) dissolved in 5 mL water and allowed to react at 37 °C for 2 hours. After 2 hours, water was added and the product was extracted with ethyl acetate. The solvent was removed in a rotary evaporator to give NFD-L1 as a white solid in about 85% yield (>95% purity). An exemplary mass spectrum is shown in Figure 34.
  • a human patient determined to have MCI based on an MMSE score is given nitroso-nifedipine at a dosage of 1000 mg per day. Nitroso-nifedipine is given as tablets for oral administration by patient three times daily.
  • Another human patient determined to have early stage Alzheimer's disease
  • EAD based on a CDR score is given nitroso-nifedipine at a dosage of 800 mg per day. Nitroso-nifedipine is given as tablets for oral administration by patient three times daily.
  • a human patient determined to have MCI based on the level of PDS/TTR complex in a fluid sample obtained from the patient is given nitroso-nifedipine at a dosage of 1000 mg per day. Nitroso-nifedipine is given as tablets for oral administration by patient four times daily.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the claims or from relevant portions of the description are introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • the claims recite a composition, it is to be understood that methods of using the composition for any of the purposes disclosed herein are included, and methods of making the composition according to any of the methods of making disclosed herein or other methods known in the art are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.
  • the invention encompasses compositions made according to any of the methods for preparing compositions disclosed herein.

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Abstract

La présente invention concerne, entre autres, des compositions thérapeutiques et des méthodes permettant de traiter, de ralentir ou de prévenir efficacement une maladie neurologique (par exemple une maladie neurodégénérative comme le trouble cognitif léger (TCL) ou la maladie d'Alzheimer) en particulier en faisant appel à une quantité thérapeutiquement efficace de nifédipine, ou de dérivés oxydés ou nitrosés de nifédipine, de lactame (par exemple un composé de formule (Ic) ou (Ic-i), par exemple le NFD-L1), de thyroxine (T4), de triiodothyronine (T3) et de combinaisons de ces substances.
PCT/US2010/057287 2010-05-13 2010-11-18 Traitement du tcl et de la maladie d'alzheimer WO2011142778A1 (fr)

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AU2010353287A AU2010353287A1 (en) 2010-05-13 2010-11-18 Treatment of MCI and Alzheimer's disease
EP10851531.3A EP2568811A4 (fr) 2010-05-13 2010-11-18 Traitement du tcl et de la maladie d'alzheimer
CN2010800680043A CN102984938A (zh) 2010-05-13 2010-11-18 轻度认知障碍(mci)和阿尔茨海默氏症的治疗方法
CA2799162A CA2799162A1 (fr) 2010-05-13 2010-11-18 Traitement du tcl et de la maladie d'alzheimer
JP2013510067A JP2013526518A (ja) 2010-05-13 2010-11-18 Ｍｃｉおよびアルツハイマー病の処置

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PCT/US2010/034721 WO2010132671A1 (fr) 2009-05-15 2010-05-13 Traitement du trouble cognitif léger et de la maladie d'alzheimer
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140328856A1 (en) * 2013-05-06 2014-11-06 Baxter International Inc. Treatment of alzheimer's disease subpopulations with pooled immunoglobulin g
WO2020146236A1 (fr) * 2019-01-07 2020-07-16 Cenna Biosciences Inc. Nouveaux peptides et utilisations associées

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015116060A1 (fr) * 2014-01-29 2015-08-06 Bristol-Myers Squibb Company Inhibiteurs d'aryl-lactame kinase
CN106177046A (zh) * 2016-08-29 2016-12-07 杨添福 一种基于普立宁钾开发的神经认知障碍治疗药物及其制备方法
CN106645505A (zh) * 2016-11-18 2017-05-10 中国医科大学 可实现glt‑1蛋白鉴定及绝对定量的试剂盒及测定方法
CN107022019B (zh) * 2016-11-24 2020-10-30 桂林医学院 一种用于脑内降铁除自由基的多肽、制备方法与应用
CN106636388A (zh) * 2016-12-15 2017-05-10 湖南中能荆卫生物科技有限公司 用于亨廷顿病诊断的基因及其应用以及由其编码的蛋白和蛋白的应用
CN108191966B (zh) * 2018-01-11 2020-10-27 桂林医学院 一种含导肽可穿越血脑屏障螯合脑内铁降自由基的多肽
JP7321017B2 (ja) * 2019-07-17 2023-08-04 東海物産株式会社 機能性食品

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3917832A (en) * 1971-05-28 1975-11-04 Merck Patent Gmbh Compositions comprising d-thyroxine and d-triiodothyronine
US6558650B1 (en) * 1998-04-08 2003-05-06 Oregon Health And Science University Enhancement of cellular gallium uptake
WO2008109613A1 (fr) * 2007-03-05 2008-09-12 Wyeth Dérivés de benzo[c][2,7]naphtyridine et leur utilisation en tant qu'inhibiteurs de kinase
US20100029654A1 (en) * 2006-03-23 2010-02-04 Mount Sinai School Of Medicine Cardiovascular compositions and use of the same for the treatment of alzheimer's disease

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8002A (en) * 1851-03-25 Upright pianoforte
US6489319B2 (en) * 1999-08-16 2002-12-03 Revaax Pharmaceuticals, Llc Neurotherapeutic use of carboxypeptidase inhibitors
EP1343501A4 (fr) * 2000-11-21 2004-12-15 Howard Zik Utilisation de bloqueurs du canal calcium a la 1,4-dihydropyridine pour traiter des atteintes neurologiques imputables au virus de l'herpes
JP2007512338A (ja) * 2003-11-21 2007-05-17 メモリー・ファーマシューティカルズ・コーポレイション Ｌ型カルシウムチャンネルブロッカーとコリンエステラーゼ阻害剤を用いた組成物及び処置方法
ATE526965T1 (de) * 2005-04-15 2011-10-15 Res & Innovation S P A Verfahren zur prävention, verzögerung oder umkehr von abnormer amyloid-ablagerung
CA2631343C (fr) * 2005-12-02 2014-02-11 Mochida Pharmaceutical Co., Ltd. La combination d'acides omega-3 et d'hormone thyroide pour le traitement de la maladie d'alzheimer
EP2018186A2 (fr) * 2006-04-11 2009-01-28 Ordway Research Institute, Inc. Nanoparticule et formes polymères d'analogues et d'antagonistes de l'hormone thyroïdienne et leurs formulations
AU2009295308A1 (en) * 2008-09-25 2010-04-01 Merck Canada Inc. Beta-carboline sulphonylurea derivatives as EP4 receptor antagonists
TW201103907A (en) * 2009-03-20 2011-02-01 Lundbeck & Co As H Amide derivatives as neuropeptide Y5 receptor ligands

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3917832A (en) * 1971-05-28 1975-11-04 Merck Patent Gmbh Compositions comprising d-thyroxine and d-triiodothyronine
US6558650B1 (en) * 1998-04-08 2003-05-06 Oregon Health And Science University Enhancement of cellular gallium uptake
US20100029654A1 (en) * 2006-03-23 2010-02-04 Mount Sinai School Of Medicine Cardiovascular compositions and use of the same for the treatment of alzheimer's disease
WO2008109613A1 (fr) * 2007-03-05 2008-09-12 Wyeth Dérivés de benzo[c][2,7]naphtyridine et leur utilisation en tant qu'inhibiteurs de kinase

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"GPR3: a novel Alzheimer drug target", GALAPAGOS NV WEB SLIDE PRESENTATION, 13 February 2009 (2009-02-13), pages 1 - 22, Retrieved from the Internet <URL:http://www.glpg.com/pdf/Galapagos-GPR3-background-20090213.pdf> [retrieved on 20110109] *
CACQUEVEL ET AL.: "Cytokines in neuroinflammation and Alzheimer's disease.", CURR DRUG TARGETS, vol. 5, no. 6, August 2004 (2004-08-01), pages 529 - 534, XP008150242, Retrieved from the Internet <URL:http://www.ncbi.nim.nih.gov/pubmed/15270199> [retrieved on 20110109] *
HONG ET AL.: "Crystal Structure of Memapsin 2 (Beta-Secretase) in Complex with an Inhibitor OM00-3", BIOCHEMISTRY, vol. 41, 2002, pages 10963 - 10967, XP002349266 *
See also references of EP2568811A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140328856A1 (en) * 2013-05-06 2014-11-06 Baxter International Inc. Treatment of alzheimer's disease subpopulations with pooled immunoglobulin g
WO2020146236A1 (fr) * 2019-01-07 2020-07-16 Cenna Biosciences Inc. Nouveaux peptides et utilisations associées
CN114437173A (zh) * 2019-01-07 2022-05-06 森纳生物科学公司 新型肽及其用途

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JP2013526518A (ja) 2013-06-24
EP2568811A1 (fr) 2013-03-20

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