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Dipeptide apoptosis inhibitors and the use thereof

a technology of apoptosis inhibitors and dipeptides, which is applied in the field of medicinal chemistry, can solve the problems of no inhibitors with good efficacy (icsub>50, sub>1 m) in whole-cell models of apoptosis, and achieves potent inhibitors of apoptosis, potent inhibitors of antifas-induced lethality, and robust neuroprotective effects

Inactive Publication Date: 2005-09-01
KEANA JOHN +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] The invention relates to the discovery that the dipeptide-based caspase inhibitors represented by Formula I, though less potent in enzyme assays than tri- and tetrapeptide inhibitors on the enzymes, are surprisingly potent inhibitors of apoptosis in cell based systems. These compounds are systemically active in vivo and are potent inhibitors of antiFas-induced lethality in a mouse liver apoptosis model and have robust neuroprotective effects in a rat model of ischemic stroke.
[0016] The invention also relates to the use of the dipeptides of the invention for reducing, preventing or treating maladies in which apoptotic cell death is either a causative factor or a result. Examples of uses for the present invention include protecting the nervous system following focal ischemia and global ischemia; treating neurodegenerative disorders such as Alzheimer's disease, Huntington's Disease, prion diseases, Parkinson's Disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, telangiectasia, and spinobulbar atrophy; treating heart disease including myocardial infarction, congestive heart failure and cardiomyopathy; treating retinal disorders; treating autoimmune disorders including lupus erythematosus, rheumatoid arthritis, type I diabetes, Sjögren's syndrome and glomerulonephritis; treating polycystic kidney disease and anemia / erythropoiesis; treating immune system disorders, including AIDS and SCIDS; reducing or preventing cell, tissue and organ damage during transplantation; reducing or preventing cell line death in industrial biotechnology; reducing or preventing alopecia (hair loss); and reducing the premature death of skin cells.
[0017] The present invention provides pharmaceutical compositions comprising a compound of Formula I in an effective amount to reduce apoptotic cell death in an animal.
[0018] The present invention also provides preservation or storage solutions for mammalian organs or tissue, or growth media for mammalian or yeast cells, wherein an effective amount of a compound of Formula I is included in said solutions or media in order to reduce apoptotic cell death in said organs, tissue or cells.

Problems solved by technology

However, in contrast to their potency in vitro, no inhibitors with good efficacy (IC50Chem. Biol. 5:R97-103 (1998)).

Method used

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  • Dipeptide apoptosis inhibitors and the use thereof
  • Dipeptide apoptosis inhibitors and the use thereof
  • Dipeptide apoptosis inhibitors and the use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

t-Butyl 5-fluoro-4-hydroxy-3-nitropentanoate

[0100] A solution of oxalic acid (1.9 mL, 21.8 mmol) in dry CH2Cl2 (100 mL) was cooled to −78° C., a solution of DMSO (3.0 mL, 42.3 mmol) in dry CH2Cl2 (10 mL) was added with stirring in such a rate that the temperature was kept at −50 to −60° C. After 5 min stirring, a solution of 2-fluoroethanol (1.2 mL, 18.4 mmol) in dry CH2Cl2 (10 mL) was added, and stirring was continued for an additional 15 min, then dry Et3N (13.5 mL) was added. The reaction mixture was stirred for 15 min, then allowed to warm to rt. To the reaction mixture was added a solution of t-butyl 3-nitropropionate (2.87 g, 16.38 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at rt for 3 h, then poured into water (100 mL). The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×50 mL). The CH2Cl2 solution was washed with brine, dried and evaporated. The residue was purified by chromatography twice over silica gel (hexane-EtOAc, 7:3) to give 9...

example 2

t-Butyl 3-amino-5-fluoro-4-hydroxy-pentanoate

[0101] To a solution of t-butyl 5-fluoro-4-hydroxy-3-nitropentanoate (950 mg, 4.0 mmol) in MeOH (20 mL) was added Raney Ni (about 200 mg), the mixture was shaken under H2 (30-35 psi) at rt for 18 h. It was filtered and the catalyst was washed with MeOH (2×10 mL). The MeOH solution was evaporated and the residue was purified by chromatography over silica gel (EtOAc-MeOH, 10:1) to give 840 mg (96%) of the titled compound as a yellowish viscous oil. 1HNMR (CDCl3), 1.450 (s, 9H), 2.12 (bs, 3H, OH and NH2), 2.28-2.38 (m, 1H), 2.47-2.57 (m, 1H), 3.24-3.30 (m, 1H), 3.54-3.76 (m, 1H), 4.38-4.48 (m, 1H), 4.54-4.61 (m, 1H).

example 3

t-Butyl 3-(Cbz-Val-amido)-5-fluoro-4-4-hydroxy-pentanoate

[0102] To a solution of Cbz-Valine (396 mg, 1.58 mmol) in THF (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (300 mg, 1.57 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (240 mg, 1.57 mmol) and dimethylaminopyridine (DMAP) 129 mg 1.06 mmol). The resulting mixture was stirred for 5 min, then was added a solution of t-butyl 3-amino-5-fluoro-4-hydroxy-pentanoate (215 mg, 1.04 mmol) in THF (10 mL) and it was stirred at rt for 18 h. The mixture was filtered and the THF solution was evaporated, and the residue was purified by chromatography over silica gel (hexane-EtOAc, 3:2) to give 290 mg (68%) of the titled compound as a white solid. 1HNMR (CDCl3), 0.905 (d, 3H, J=7), 0.965 (d, 3H, J=7), 1.428 (s, 9H), 2.07-2.16 (m, 1H), 2.50-2.57 (m, 1H), 2.64-2.70 (m, 1H), 3.52 (bs, 1H, OH), 3.92-3.96 (m, 2H), 4.20-4.27 (m, 1H), 4.40 (bs, 1H),4.49 (bs, 1H), 5.10 (s, 2H), 5.31-5.4 (m, 1H, NH), 6.86-6.93 (m, 1H, NH), 7.350(...

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Abstract

The present invention is directed to novel dipeptides thereof, represented by the 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.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention is in the field of medicinal chemistry. In particular, the invention relates to dipeptides which are potent inhibitors of apoptosis. The invention also relates to the use of these dipeptides for reducing or treating apoptotic cell death. [0003] 2. Description of Background Art [0004] Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis et al., Dev. 112:591-603 (1991); Vaux et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00C07C237/22C07C271/22C07C323/60C07D233/54C07D277/16C07K5/06
CPCA61K38/00C07C237/22C07C271/22C07C323/60Y10S514/885C07D277/16C07K5/06191C12N2810/40C07D233/64
Inventor KEANA, JOHNCAI, SUIGUASTELLA, JOHNYANG, WUDREWE, JOHNWEBER, ECKARD
Owner KEANA JOHN
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