Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/64—Cyclic peptides containing only normal peptide links
  • C07K7/645—Cyclosporins; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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

• R represents a carboxy or alkyloxycarbonyl radical; a radical -NR 1 R 2 in which Ri and R2 are the same or different and represent hydrogen, alkyl, C 2-4 alkenyl, C 3-6 CyClOa I kyl, phenyl (optionally substituted by halogen, alkoxy, alkoxycarbonyl, amino, alkylamino or diaikylamino) or a benzyl or saturated or unsaturated heterocyclyl radical containing 5 or 6 ring atoms and 1 to 3 heteroatoms, or in which Riand R 2 form together with the nitrogen atom to which they are attached a saturated or unsaturated heterocycle containing 4 to 6 ring atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur and optionally substituted by alkyl, phenyl or benzyl; a radical of formula
• R, R 2 wherein Ri and R 2 are as defined above, R3 represents hydrogen or an alkyl radical and n is a whole number from 2 to 4, and wherein alkyl denotes straight or branched chain alkyl containing from 1 to 4 carbon atoms; C is MeLeu or or 4-hydroxy-MeLeu; and the pharmaceutically acceptable salts thereof.
• the invention provides use of a nonimmunosuppresive, cyclophilin-binding cyclosporin in the manufacture of a medicament for treating or preventing pathological conditions associated with AB secretion such as Alzheimer's Disease, Parkinson's Disease, tauopathies, prion diseases, frontotemporal dementia, striatonigral degeneration, Lewy body dementia, Huntington's disease, Pick's disease, amyloidosis, and other neurodegenerative disorders associated with excess AB production.
• pathological conditions associated with AB secretion such as Alzheimer's Disease, Parkinson's Disease, tauopathies, prion diseases, frontotemporal dementia, striatonigral degeneration, Lewy body dementia, Huntington's disease, Pick's disease, amyloidosis, and other neurodegenerative disorders associated with excess AB production.
• the appropriate dosage will, of course, vary depending upon, for example, the particular molecule of the invention to be employed, the mode of administration and the nature and severity of the condition being treated.
• HEK cells are transiently transfected with CyD or CPZ along with APPwt for 24 hours.
• Cells are fixed, permeabilized, and stained using the Caspase-3 apoptosis kit from BD Biosciences (#550914).
• FITC stained cells are gated from > 10 1 and measured as cells positive for active caspase-3. Forward and side light scatter are also examined to check the health of the cell population.
• HEK stable cells are treated with cyclosporin A 1 Sangliferhin A, FK506 or N-methyl-4-valine-cyclosporin and the IC 50 for C99 cleavage are determined.
• GALVP alone may be as the negative control.
• the GALVP ICsofor cyclosporin A, N-methyl- 4-valine-cyclosporin Sangliferhin A, and FK506 is 6.9, 9.9, >20, and >20 ⁇ M, respectively, indicating a clear window between inhibition of C99 cleavage and cell viability, since these compounds are not toxic until > 40 ⁇ M.
• cyclosporin A, N-methyl-4-valine- cyclosporin Sangliferhin A all inhibit C99 cleavage at 0.71 , 0.87, and 0.85 ⁇ M, and inhibit Notch cleavage at 1.7, 2.7 and 3.2 ⁇ M, respectively.
• FK506 has no effect on C99 or Notch cleavage. Therefore ligands that can bind CyD strongly inhibit C99 and Notch cleavage suggesting GACE activity is being inhibited.

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• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Psychology (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Epidemiology (AREA)
• Biochemistry (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

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• 2005
  • 2005-07-12 CA CA002573400A patent/CA2573400A1/en not_active Abandoned
  • 2005-07-12 AU AU2005261838A patent/AU2005261838A1/en not_active Abandoned
  • 2005-07-12 JP JP2007520737A patent/JP2008512351A/ja active Pending
  • 2005-07-12 RU RU2007105141/15A patent/RU2007105141A/ru not_active Application Discontinuation
  • 2005-07-12 EP EP05774275A patent/EP1893226A1/en not_active Withdrawn
  • 2005-07-12 CN CNA2005800237213A patent/CN1984670A/zh active Pending
  • 2005-07-12 BR BRPI0513317-3A patent/BRPI0513317A/pt not_active IP Right Cessation
  • 2005-07-12 KR KR1020077000882A patent/KR20070036127A/ko not_active Application Discontinuation
  • 2005-07-12 MX MX2007000502A patent/MX2007000502A/es not_active Application Discontinuation
  • 2005-07-12 WO PCT/EP2005/007556 patent/WO2006005580A1/en active Application Filing
• 2009
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