CA2306692A1 - Dipeptide apoptosis inhibitors and the use thereof - Google Patents
Dipeptide apoptosis inhibitors and the use thereof Download PDFInfo
- Publication number
- CA2306692A1 CA2306692A1 CA002306692A CA2306692A CA2306692A1 CA 2306692 A1 CA2306692 A1 CA 2306692A1 CA 002306692 A CA002306692 A CA 002306692A CA 2306692 A CA2306692 A CA 2306692A CA 2306692 A1 CA2306692 A1 CA 2306692A1
- Authority
- CA
- Canada
- Prior art keywords
- ch2f
- asp
- compound
- cell death
- ome
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010016626 Dipeptides Proteins 0.000 title abstract 2
- 229940088872 Apoptosis inhibitor Drugs 0.000 title 1
- 239000000158 apoptosis inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 26
- 230000030833 cell death Effects 0.000 claims abstract 14
- 210000000056 organ Anatomy 0.000 claims abstract 7
- 238000000034 method Methods 0.000 claims 24
- 210000001519 tissue Anatomy 0.000 claims 9
- 241000124008 Mammalia Species 0.000 claims 5
- 201000004384 Alopecia Diseases 0.000 claims 4
- 241001465754 Metazoa Species 0.000 claims 4
- 210000004027 cell Anatomy 0.000 claims 4
- 230000005855 radiation Effects 0.000 claims 4
- 210000003169 central nervous system Anatomy 0.000 claims 3
- 230000003676 hair loss Effects 0.000 claims 3
- 208000024963 hair loss Diseases 0.000 claims 3
- 208000028867 ischemia Diseases 0.000 claims 3
- 210000001428 peripheral nervous system Anatomy 0.000 claims 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims 2
- 208000036142 Viral infection Diseases 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 235000013601 eggs Nutrition 0.000 claims 2
- 210000004209 hair Anatomy 0.000 claims 2
- 210000000987 immune system Anatomy 0.000 claims 2
- 239000002609 medium Substances 0.000 claims 2
- 210000004165 myocardium Anatomy 0.000 claims 2
- 239000000651 prodrug Substances 0.000 claims 2
- 229940002612 prodrug Drugs 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- 210000001116 retinal neuron Anatomy 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 210000003491 skin Anatomy 0.000 claims 2
- 230000037380 skin damage Effects 0.000 claims 2
- 208000011580 syndromic disease Diseases 0.000 claims 2
- 230000009385 viral infection Effects 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 208000030507 AIDS Diseases 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 206010003694 Atrophy Diseases 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 claims 1
- 208000010496 Heart Arrest Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 208000023105 Huntington disease Diseases 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 208000024777 Prion disease Diseases 0.000 claims 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 206010064930 age-related macular degeneration Diseases 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- 206010068168 androgenetic alopecia Diseases 0.000 claims 1
- 208000007502 anemia Diseases 0.000 claims 1
- 230000037444 atrophy Effects 0.000 claims 1
- 238000003287 bathing Methods 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 230000036770 blood supply Effects 0.000 claims 1
- 230000010261 cell growth Effects 0.000 claims 1
- 238000002512 chemotherapy Methods 0.000 claims 1
- 230000034994 death Effects 0.000 claims 1
- 201000011304 dilated cardiomyopathy 1A Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 230000002996 emotional effect Effects 0.000 claims 1
- 230000010437 erythropoiesis Effects 0.000 claims 1
- 230000003492 excitotoxic effect Effects 0.000 claims 1
- 231100000063 excitotoxicity Toxicity 0.000 claims 1
- 230000004720 fertilization Effects 0.000 claims 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims 1
- 239000001963 growth medium Substances 0.000 claims 1
- 210000003780 hair follicle Anatomy 0.000 claims 1
- 210000002865 immune cell Anatomy 0.000 claims 1
- 230000008629 immune suppression Effects 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 208000033065 inborn errors of immunity Diseases 0.000 claims 1
- 238000001802 infusion Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 208000014674 injury Diseases 0.000 claims 1
- 230000004410 intraocular pressure Effects 0.000 claims 1
- 206010025135 lupus erythematosus Diseases 0.000 claims 1
- 208000002780 macular degeneration Diseases 0.000 claims 1
- 210000004962 mammalian cell Anatomy 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 claims 1
- 210000002569 neuron Anatomy 0.000 claims 1
- 239000002674 ointment Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 208000030761 polycystic kidney disease Diseases 0.000 claims 1
- 230000002028 premature Effects 0.000 claims 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- -1 t-butyloxycarbonyl Chemical group 0.000 claims 1
- 230000008736 traumatic injury Effects 0.000 claims 1
- 210000005253 yeast cell Anatomy 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract 2
- 230000006907 apoptotic process Effects 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/16—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2810/00—Vectors comprising a targeting moiety
- C12N2810/40—Vectors comprising a peptide as targeting moiety, e.g. a synthetic peptide, from undefined source
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Psychiatry (AREA)
- Genetics & Genomics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Transplantation (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
The present invention is directed to novel dipeptides thereof, represented by general Formula (I) where R1-R3 and AA are defined herein. The present invention relates to the discovery that compounds having Formula (I) are potent inhibitors of apoptotic cell death. Therefore, the inhibitors of this invention can retard or block cell death in a variety of clinical conditions in which the loss of cells, tissues or entire organs occurs.
Claims (32)
1. A compound having the Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is an N-terminal protecting group; AA is a residue of any natural .alpha.-amino acid, or .beta.-amino acid; R2 is H or CH2R4, where R4 is an electronegative leaving group, and R3 is alkyl or H; provided that AA is not His, Tyr, Pro or Phe.
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is an N-terminal protecting group; AA is a residue of any natural .alpha.-amino acid, or .beta.-amino acid; R2 is H or CH2R4, where R4 is an electronegative leaving group, and R3 is alkyl or H; provided that AA is not His, Tyr, Pro or Phe.
2. A compound according to claim 1, wherein R1 is t-butyloxycarbonyl, acetyl or benzyloxycarbonyl.
3. A compound according to claim 1, wherein AA is Gly, Thr, Glu, Lys, Arg, Ser, Asn, Gln, Val, Ala, Leu, Ile, Met, or .beta.-Ala.
4. A compound according to claim 1, wherein R2 is H or CH2F.
5. A compound according to claim l, wherein R3 is H or C1-6 alkyl.
6. A compound according to claim 1, wherein said compound has the Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, wherein R1 is an N-terminal protecting group; AA is a residue of any natural .alpha.-amino acid, or .beta.-amino acid; and R3 is alkyl or H; provided that AA is not His, Tyr, Pro or Phe.
or a pharmaceutically acceptable salt or prodrug thereof, wherein R1 is an N-terminal protecting group; AA is a residue of any natural .alpha.-amino acid, or .beta.-amino acid; and R3 is alkyl or H; provided that AA is not His, Tyr, Pro or Phe.
7. A compound according to claim 1, wherein said compound is selected from the group consisting of:
Boc-Ala-Asp-CH2F, Boc-Val-Asp-CH2F, Boc-Leu-Asp-CH2F, Ac-Val-Asp-CH2F, Ac-Ile-Asp-CH2F, Ac-Met-Asp-CH2F, Cbz-Val-Asp-CH2F, Cbz-.beta.-Ala-Asp-CH2F, Cbz-Leu-Asp-CH2F, Cbz-Ile-Asp-CH2F, Boc-Ala-Asp(OMe)-CH2F, Boc-Val-Asp(OMe)-CH2F, Boc-Leu-Asp(OMe)-CH2F, Ac-Val-Asp(OMe)-CH2F, Ac-Ile-Asp(OMe)-CH2F, Ac-Met-Asp(OMe)-CH2F, Cbz-Val-Asp(OMe)-CH2F, Cbz-.beta.-Ala-Asp(OMe)-CH2F, Cbz-Leu-Asp(OMe)-CH2F, and Cbz-Ile-Asp(OMe)-CH2F.
Boc-Ala-Asp-CH2F, Boc-Val-Asp-CH2F, Boc-Leu-Asp-CH2F, Ac-Val-Asp-CH2F, Ac-Ile-Asp-CH2F, Ac-Met-Asp-CH2F, Cbz-Val-Asp-CH2F, Cbz-.beta.-Ala-Asp-CH2F, Cbz-Leu-Asp-CH2F, Cbz-Ile-Asp-CH2F, Boc-Ala-Asp(OMe)-CH2F, Boc-Val-Asp(OMe)-CH2F, Boc-Leu-Asp(OMe)-CH2F, Ac-Val-Asp(OMe)-CH2F, Ac-Ile-Asp(OMe)-CH2F, Ac-Met-Asp(OMe)-CH2F, Cbz-Val-Asp(OMe)-CH2F, Cbz-.beta.-Ala-Asp(OMe)-CH2F, Cbz-Leu-Asp(OMe)-CH2F, and Cbz-Ile-Asp(OMe)-CH2F.
8. A compound according to claim 1, wherein said compound is selected from the group consisting of:
Cbz-Val-Asp-CH2F, and Cbz-Val-Asp(OMe)-CH2F.
Cbz-Val-Asp-CH2F, and Cbz-Val-Asp(OMe)-CH2F.
9. A pharmaceutical composition, comprising a compound of claim 1, and a pharmaceutically acceptable carrier.
10. A method of inhibiting cell death or a cell or tissue, comprising contacting said cell or tissue with an effective amount of a compound of claim 1.
11. A method of treating or ameliorating cell death in the central and peripheral nervous system, retinal neurons, cardiac muscle or immune system cells of an animal, comprising administering to the animal in need of such treatment or ameliorating an effective amount of a compound of claim 1.
12. The method of claim 11, wherein said cell death is in the central or peripheral nervous system, and is due to one of:
(a) a condition of ischemia and excitotoxicity selected from the group consisting of focal ischemia due to stroke and global ischemia due to cardiac arrest;
(b) traumatic injury;
(c) viral infection;
(d) radiation-induced nerve cell death; or (e) a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, Parkinson's Disease, a prion disease, multiple sclerosis, amyotrophic lateral sclerosis, and spinobulbar atrophy.
(a) a condition of ischemia and excitotoxicity selected from the group consisting of focal ischemia due to stroke and global ischemia due to cardiac arrest;
(b) traumatic injury;
(c) viral infection;
(d) radiation-induced nerve cell death; or (e) a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, Parkinson's Disease, a prion disease, multiple sclerosis, amyotrophic lateral sclerosis, and spinobulbar atrophy.
13. The method of claim 11, wherein said cell death is in the central or peripheral nervous system, and is due to expansion of trinucleotide repeats of specific genes.
14. The method of claim 11, wherein said cell death is due to Huntington's Disease.
15. The method of claim 11, wherein said cell death is in cardiac muscle tissue, and is due to myocardial infarction, congestive heart failure, cardiomyopathy or viral infection of the heart.
16. The method of claim 11, wherein said cell death is in retinal neurons and is due to increased intraocular pressure, age-related macular degeneration or retinitis pigmentosa.
17. The method of claim 11, wherein said cell death is in the immune system, and is due to an immune deficiency disorder selected from the group consisting of acquired immune deficiency syndrome, severe combined immune deficiency syndrome and radiation-induced immune suppression.
18. The method of claim 11, wherein said cell death is due to an autoimmune disorder selected from the group consisting of lupus erythematosus, rheumatoid arthritis and type I diabetes.
19. The method of claim 11, wherein said cell death is due to type I
diabetes.
diabetes.
20. A method of treating or preventing polycystic kidney disease or anemia/erythropoiesis in an animal, comprising administering to the animal in need of such treatment or preventing an effective amount of a compound of claim 1.
21. A method of protecting a mammalian organ or tissue from cell death due to deprivation of normal blood supply, comprising contacting said organ or tissue with an effective amount of a compound of claim 1.
22. The method of claim 21, wherein said organ or tissue is present in a storage medium prior to transplant into a mammal.
23. The method of claim 21, wherein said contacting comprises infusion of said compound into the organ or tissue, or bathing of said organ or tissue in a storage medium which comprises said compound.
24. A method of reducing or preventing cell death in a donor organ or tissue after it has been transplanted into a host due to the effects of host immune cells, comprising administering to said host in need thereof an effective amount of a compound of claim 1.
25. A method of reducing or preventing the death of mammalian sperm or eggs used in in vitro fertilization procedures, comprising contacting said sperm or egg with an effective amount of a compound of claim 1.
26. A method of extending the lifespan of a mammalian or yeast cell line, comprising contacting said cell line with a compound of claim 1.
27. The method of claim 26, wherein said contacting comprises including said compound in a cell growth medium.
28. A method of treating or ameliorating hair loss or premature graying of the hair in a mammal, comprising contacting the hair or hair follicles of the mammal in need thereof with a compound of claim 1.
29. The method of claim 28, wherein hair loss is treated, and said hair loss is due to male-pattern baldness, radiation, chemotherapy or emotional stress.
30. A method of treating or ameliorating skin damage of a mammal due to exposure to high levels of radiation, heat or chemicals, comprising applying to the skin of the mammal in need thereof with a compound of claim 1.
31. The method of claim 30, wherein said compound is applied as part of an ointment.
32. The method of claim 30, wherein said skin damage is due to acute over-exposure to the sun, and wherein said treating reduces blistering and peeling of the skin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6167697P | 1997-10-10 | 1997-10-10 | |
| US60/061,676 | 1997-10-10 | ||
| PCT/US1998/021232 WO1999018781A1 (en) | 1997-10-10 | 1998-10-09 | Dipeptide apoptosis inhibitors and the use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2306692A1 true CA2306692A1 (en) | 1999-04-22 |
| CA2306692C CA2306692C (en) | 2010-09-21 |
Family
ID=22037372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2306692A Expired - Fee Related CA2306692C (en) | 1997-10-10 | 1998-10-09 | Dipeptide apoptosis inhibitors and the use thereof |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1033910A4 (en) |
| JP (1) | JP4439111B2 (en) |
| KR (1) | KR100580333B1 (en) |
| CN (1) | CN1138472C (en) |
| AU (1) | AU741203B2 (en) |
| BR (1) | BR9814817A (en) |
| CA (1) | CA2306692C (en) |
| EA (1) | EA200000409A1 (en) |
| NO (1) | NO20001323L (en) |
| WO (1) | WO1999018781A1 (en) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6184210B1 (en) | 1997-10-10 | 2001-02-06 | Cytovia, Inc. | Dipeptide apoptosis inhibitors and the use thereof |
| CN1297354A (en) * | 1998-03-16 | 2001-05-30 | 西托维亚公司 | Dipeptide caspase inhibitors and use thereof |
| ATE333287T1 (en) * | 1998-05-29 | 2006-08-15 | Mochida Pharm Co Ltd | PROPHYLAXIS AND TREATMENT OF AUTOIMMUNE DEMYELINATING DISEASES USING FAS ANTAGONISTS |
| US7488590B2 (en) | 1998-10-23 | 2009-02-10 | Amgen Inc. | Modified peptides as therapeutic agents |
| JP3820105B2 (en) | 1998-10-23 | 2006-09-13 | キリン−アムジエン・インコーポレーテツド | Dimeric thrombopoietin peptidomimetic that binds to MP1 receptor and has platelet-forming activity |
| US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
| ATE336480T1 (en) | 1999-03-16 | 2006-09-15 | Cytovia Inc | SUBSTITUTED 2-AMINOBENZAMIN CASPASE INHIBITORS AND THEIR USE |
| BR0009610A (en) | 1999-04-09 | 2002-02-13 | Cytovia Inc | Caspase inhibitors and their use |
| CA2383002A1 (en) | 1999-08-27 | 2001-03-08 | Cytovia, Inc. | Substituted .alpha.-hydroxy acid caspase inhibitors and the use thereof |
| US6566338B1 (en) | 1999-10-12 | 2003-05-20 | Cytovia, Inc. | Caspase inhibitors for the treatment and prevention of chemotherapy and radiation therapy induced cell death |
| US6303374B1 (en) | 2000-01-18 | 2001-10-16 | Isis Pharmaceuticals Inc. | Antisense modulation of caspase 3 expression |
| DE10006889A1 (en) * | 2000-02-16 | 2001-09-06 | Procorde Gmbh | Use of inhibitors of caspase-3 or the caspase-activated deoxyribonuclease (CAD) for the treatment of heart diseases |
| YU73702A (en) | 2000-03-29 | 2006-03-03 | Vertex Pharmaceuticals Incorporated | Carbamate caspase inhibitors and uses thereof |
| EP1923386A3 (en) | 2000-03-29 | 2008-05-28 | Vertex Pharmceuticals Incorporated | Carbamate caspase inhibitors and uses thereof |
| CA2380935A1 (en) * | 2000-05-23 | 2001-11-29 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
| US20020052323A1 (en) * | 2000-08-30 | 2002-05-02 | Jinhai Wang | Quinoline-(C=O)-(multiple amino acids)-leaving group compounds for pharmaceutical compositions and reagents |
| ATE510837T1 (en) | 2000-09-13 | 2011-06-15 | Vertex Pharma | CASPASE INHIBITORS AND THEIR USE |
| US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| CN100355750C (en) | 2000-09-15 | 2007-12-19 | 沃泰克斯药物股份有限公司 | Pyrazole compounds useful as protein kinase inhibitors |
| ATE326462T1 (en) | 2000-12-21 | 2006-06-15 | Vertex Pharma | PYRAZOLE COMPOUNDS AS PROTEIN KINASE INHIBITORS |
| CA2443600A1 (en) | 2001-04-19 | 2002-10-31 | Vertex Pharmaceuticals Incorporated | Heterocyclyldicarbamides as caspase inhibitors |
| MY141867A (en) | 2002-06-20 | 2010-07-16 | Vertex Pharma | Substituted pyrimidines useful as protein kinase inhibitors |
| NZ550883A (en) | 2002-08-02 | 2008-06-30 | Vertex Pharma | Pyrazole compositions useful as inhibitors of glycogen synthase kinase-3 (GSK-3) |
| JP2006502415A (en) * | 2002-10-10 | 2006-01-19 | ベクトン・ディキンソン・アンド・カンパニー | Sample collection system with caspase inhibitor |
| US8008453B2 (en) | 2005-08-12 | 2011-08-30 | Amgen Inc. | Modified Fc molecules |
| SG166827A1 (en) | 2005-11-03 | 2010-12-29 | Vertex Pharma | Aminopyrimidines useful as kinase inhibitors |
| JP5389785B2 (en) | 2007-05-02 | 2014-01-15 | バーテックス ファーマシューティカルズ インコーポレイテッド | Thiazoles and pyrazoles useful as kinase inhibitors |
| MX2010001137A (en) | 2007-07-31 | 2010-03-31 | Vertex Pharma | Process for preparing 5-fluoro-1h-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof. |
| FR2923160B1 (en) * | 2007-11-02 | 2013-07-26 | Pasteur Institut | COMPOUNDS FOR PREVENTING OR TREATING VIRAL INFECTION. |
| MX2011002312A (en) | 2008-09-03 | 2011-04-26 | Vertex Pharma | Co-crystals and pharmaceutical formulations comprising the same. |
| CN106317161B (en) * | 2015-06-29 | 2020-05-15 | 深圳翰宇药业股份有限公司 | Preparation method of fluoromethyl ketone peptide series compounds |
| CN117045634A (en) * | 2022-05-06 | 2023-11-14 | 北京康蒂尼药业股份有限公司 | Dipeptide derivative composition and preparation method and application thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991015577A1 (en) * | 1990-04-04 | 1991-10-17 | Black, Roy, A. | INTERLEUKIN 1'beta' PROTEASE |
| EP0519748B1 (en) * | 1991-06-21 | 1998-09-02 | Merck & Co. Inc. | Peptidyl derivatives as inhibitors of interleukin-1B converting enzyme |
| EP0600880B1 (en) * | 1991-08-30 | 2004-01-07 | Vertex Pharmaceuticals Incorporated | Interleukin 1- beta protease and interleukin 1-beta protease inhibitors |
| US5462939A (en) * | 1993-05-07 | 1995-10-31 | Sterling Winthrop Inc. | Peptidic ketones as interleukin-1β-converting enzyme inhibitors |
| JPH0789951A (en) * | 1993-06-03 | 1995-04-04 | Sterling Winthrop Inc | Interleukin-1 beta transfer enzyme inhibitor |
| US5565430A (en) * | 1994-08-02 | 1996-10-15 | Sterling Winthrop Inc. | Azaaspartic acid analogs as interleukin-1β converting enzyme inhibitors |
| WO1998010778A1 (en) * | 1996-09-12 | 1998-03-19 | Idun Pharmaceuticals, Inc. | INHIBITION OF APOPTOSIS USING INTERLEUKIN-1β-CONVERTING ENZYME (ICE)/CED-3 FAMILY INHIBITORS |
-
1998
- 1998-10-09 AU AU97930/98A patent/AU741203B2/en not_active Ceased
- 1998-10-09 BR BR9814817-6A patent/BR9814817A/en not_active IP Right Cessation
- 1998-10-09 CA CA2306692A patent/CA2306692C/en not_active Expired - Fee Related
- 1998-10-09 KR KR1020007003882A patent/KR100580333B1/en not_active IP Right Cessation
- 1998-10-09 WO PCT/US1998/021232 patent/WO1999018781A1/en active IP Right Grant
- 1998-10-09 EA EA200000409A patent/EA200000409A1/en unknown
- 1998-10-09 CN CNB988100223A patent/CN1138472C/en not_active Expired - Fee Related
- 1998-10-09 EP EP98952166A patent/EP1033910A4/en not_active Withdrawn
- 1998-10-09 JP JP2000515426A patent/JP4439111B2/en not_active Expired - Fee Related
-
2000
- 2000-03-14 NO NO20001323A patent/NO20001323L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EA200000409A1 (en) | 2000-10-30 |
| CN1301131A (en) | 2001-06-27 |
| BR9814817A (en) | 2002-01-08 |
| WO1999018781A1 (en) | 1999-04-22 |
| KR20010031053A (en) | 2001-04-16 |
| JP4439111B2 (en) | 2010-03-24 |
| CN1138472C (en) | 2004-02-18 |
| AU9793098A (en) | 1999-05-03 |
| KR100580333B1 (en) | 2006-05-16 |
| AU741203B2 (en) | 2001-11-22 |
| EP1033910A1 (en) | 2000-09-13 |
| CA2306692C (en) | 2010-09-21 |
| JP2001519358A (en) | 2001-10-23 |
| NO20001323D0 (en) | 2000-03-14 |
| NO20001323L (en) | 2000-06-13 |
| EP1033910A4 (en) | 2004-11-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2306692A1 (en) | Dipeptide apoptosis inhibitors and the use thereof | |
| EP1076563B1 (en) | Dipeptide caspase inhibitors and the use thereof | |
| JP2002541237A5 (en) | ||
| JP5647995B2 (en) | Novel anti-aging peptide and cosmetic and / or pharmaceutical composition containing the same | |
| WO1993002099A1 (en) | Acylmercaptoalkanoyldipeptides, methods of preparation and their therapeutic use | |
| JPS61212598A (en) | Insulin compound | |
| KR20140026329A (en) | Cyclosporin analogs | |
| WO2006059227A1 (en) | Gem difluorinated c-glycopeptides, their preparation and their use for the preservation of biological materials and/or in cryosurgery | |
| WO2021033830A1 (en) | Peptide having hair growth promoting activity, and use thereof | |
| KR101713127B1 (en) | Peptides Having Activity for Increasing Melanin Synthesis and Inhibiting Fat Synthesis and Uses Thereof | |
| EP0409939A1 (en) | Use of polyunsaturated fatty acid derivatives in the preparation of medicaments with tyrosine kinase inhibiting activity | |
| CZ287816B6 (en) | Peptide, process of its preparation, pharmaceutical preparation in which it is comprised and use thereof | |
| FR2900656A1 (en) | GEM-DIFLUORINE C-GLYCOPEPTIDE COMPOUNDS, THEIR PREPARATION AND THEIR USE, IN PARTICULAR FOR THE PRESERVATION OF BIOLOGICAL MATERIALS | |
| US7585846B2 (en) | Compounds for delivering amino acids or peptides with antioxidant activity into mitochondria and use thereof | |
| US20060160748A1 (en) | Compounds for delivering amino acids or peptides with antioxidant activity into mitochondria and use thereof | |
| US6831162B2 (en) | Protein/polypeptide-k obtained from Momordica charantia and a process for the extraction thereof | |
| US5663148A (en) | Anaphylatoxin receptor ligands containing lipophilic residues | |
| US9365633B2 (en) | Peptide preparations and peptides with antitumour activity | |
| EP0998494B1 (en) | Pompilid wasp-derived neuropeptides | |
| PT618226E (en) | INHIBITORS OF RIBONUCLEOTIDE REDUCTASE OF HERPES VIRUSES | |
| RU94018525A (en) | SUBSTITUTED 2-HYDROXY-3 [1- (1H-IMIDAZOL-4-IL) ALKYL] -BENZOLKARBOXIMIDAMIDES, METHODS OF THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITION ON THEIR BASIS | |
| JP3887109B2 (en) | Topical skin preparation | |
| JP3972104B2 (en) | Novel hexapeptide and angiotensin converting enzyme inhibitors | |
| JPH1036289A (en) | Nerve cell or perishing inhibitor | |
| SU1703117A1 (en) | Remedy for suppressing sperm motility |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20141009 |