Inhibitors of the ICE/ced-3 family of cysteine proteases

a protease and inhibitor technology, applied in the field of inhibitors of the ice/ced3 family of cysteine proteases, can solve the problems of poor stability and rapid metabolism, unsatisfactory pharmacologic properties, poor oral absorption, etc., and achieve the effects of improving cell penetration, improving absorption and metabolic stability, and improving properties

Inactive Publication Date: 2006-04-20
IDUN PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] In general, the compounds of this invention incorporate a sulfonamido (NHSO2) or sulfinamido (NHSO) modified (N-substituted)oxamyl group as a dipeptide mimetic. The resulting compounds exhibit improved properties relative to their peptidic counterparts, for example, such as improved cell penetration or improved absorption and metabolic stability resulting in enhanced bioavailability.

Problems solved by technology

However, such inhibitors have been typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism.
These undesirable properties have hampered their development into effective drugs.

Method used

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  • Inhibitors of the ICE/ced-3 family of cysteine proteases
  • Inhibitors of the ICE/ced-3 family of cysteine proteases
  • Inhibitors of the ICE/ced-3 family of cysteine proteases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Assay for Inhibition of ICE / CED-3 Protease Family Activity

A. Determination of IC50 Values

[0155] Fluorescence enzyme assays detecting the activity of the compounds of Formula I utilizing the recombinant ICE and CPP32 enzymes are performed essentially according to Thomberry et al. (Nature 356:768:774 (1992)) and Nicholson et al. (Nature 376:37-43 (1995)) respectively, (herein incorporated by reference) in 96 well microtiter plates. The substrate is Acetyl-Tyr-Val-Ala-Asp-amino-4-methylcoumarin (AMC) for the ICE assay and Acetyl-Asp-Glu-Val-Asp-amino4-methylcoumarin for the CPP32, Mch2, Mch3 and Mch5 assays. Enzyme reactions are run in ICE buffer (25 mM HEPES, 1 mM EDTA, 0.1% CHAPS, 10% sucrose, pH 7.5) containing 2 mM DTT at room temperature in duplicate. The assays are performed by mixing the following components: [0156] 50 μL ICE, Mch2, Mch5, CPP32 (18.8, 38, 8.1 and 0.153 nM concentrations, respectively) or Mch3 (1 unit) enzyme in ICE buffer containing either 8.0 (ICE, Mch2, Mch...

example 2

3S)-N-methanesulfonyl-3-[N-(N′-(2-t-butylphenyl)oxamyl)valinyl]amino-5-(2′,3′,5′,6′-tetrafluorophenoxy)-4-oxapentanamide

[0161]

[0162] Compound No. 1 was made according to the following reaction scheme, the procedures for which are set forth below.

Bromomethylketone 2:

[0163] 4-Methylmorpholine (0.76 mL, 6.9 mmol) was added to a solution of Fmoc-Asp(OBn)-OH (1) (2.05 g, 4.62 mmol) in 50 mL of dry THF at −10° C. under an atmosphere of nitrogen, followed by the addition of isobutyl chloroformate (0.90 mL, 6.9 mmol), and the solution was stirred for 20 minutes. The resulting white precipitate was removed by filtration and the filtrate was cooled to 0° C. In a separate flask, 1-methyl-3-nitro-1-nitrosoguanidine (1.10 g, 7.44 mmol) was added to a vigorously stirred mixture of diethyl ether (14 mL) and 40% KOH (8 mL) at 0° C. The resulting mixture was stirred for 10 minutes and the layers were allowed to separate. The ether layer was transferred via plastic pipette to the mixed anhydride...

example 3

Representative Compounds

[0175] The representative compounds listed in the following Table I may be made according to the procedures set forth in Example 2.

TABLE 1Representative CompoundsCpdABR11NHCH(CH2CH(CH3)2)COH1-naphthyl2NHCH(CH2CH(CH3)2)COCH2F1-naphthyl3NHCH(CH(CH3)2)COCH2F1-naphthyl4NHCH(CH(CH3)2)COCH2OCO(2,4-diCl-Ph)1-naphthyl5NHCH(CH(CH3)2)COCH2O(2,6-diF-Ph)1-naphthyl6NHCH(CH(CH3)2)COCH2O(2,4,6-triF-Ph)1-naphthyl7NHCH(CH(CH3)2)COCH2O(2,3,5,6-tetraF-Ph)1-naphthyl8NHCH(CH(CH3)2)COCH2O(6-Me-2-pyron-4-yl)1-naphthyl9NHCH(CH(CH3)2)COCH2O(2-Ph-5,6-1-naphthylbenzopyran-4-on-3-yl)10NHCH(CH(CH3)2)COCH2OPO(Me)Ph1-naphthyl11NHCH(CH(CH3)2)COCH2OPOPh21-naphthyl12NHCH(CH(CH3)2)COCH2O(2-CF3-pyrimidin-4-1-naphthylyl)13NHCH(CH(CH3)2)COCH2O(5-CO2Me-isoxazol-1-naphthyl3-yl)14NHCH(CH(CH3)2)COCH2OPO(Me)(1-naphthyl)1-naphthyl15NHCH(CH2CH(CH3)2)COCH2OPOPh21-naphthyl16NHCH(CH2CH(CH3)2)COCH2OCO(2,6-diCl-Ph)1-naphthyl17NHCH(CH2CH(CH3)2)COCH2O(2,4,6-triF-Ph)1-naphthyl18NHCH(CH2CH(CH3)2)COCH2O(2,3,5,...

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Abstract

This invention is directed to novel oxamyl dipeptide ICE / ced-3 family inhibitor compounds having the following structure: wherein A, B, R, R1, R1′ p and q are as defined herein. The invention is also directed to pharmaceutical compositions containing one or more of these compounds, as well as to the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury, and for the preservation of organs that are to undergo a transplantation procedure.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 09 / 482,813, filed Jan. 13, 2000 (which application is incorporated herein by reference in its entirety).BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme and related proteases (“ICE / ced-3 family of cysteine proteases”), as well as pharmaceutical compositions comprising these compounds and to methods of using such pharmaceutical compositions. [0004] 2. Description of the Related Art [0005] Interleukin 1 (“IL-1”) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al., Immunology To...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/06C07K5/06C12N9/99A61K31/18A61K31/404A61K31/445A61K31/662A61K38/00A61K38/55A61P7/00A61P7/06A61P9/10A61P11/00A61P19/08A61P25/00A61P29/00A61P31/00A61P35/00A61P37/00A61P37/02A61P41/00A61P43/00C07C311/51C07D209/42C07D211/60C07K5/065C12N5/06
CPCA61K38/05C07C311/51C07K5/06026C07K5/06034C07K5/06078C07K5/06191A61P7/00A61P7/06A61P9/10A61P11/00A61P19/08A61P25/00A61P29/00A61P31/00A61P35/00A61P37/00A61P37/02A61P41/00A61P43/00C07K5/0202
Inventor TERNANSKY, ROBERT J.GLADSTONE, PATRICIA L.TOMASELLI, KEVIN J.CHAO, BINLINTON, STEVEN D.
Owner IDUN PHARMA INC
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