Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Patent
1996-08-23
1999-11-02
Weber, Jon P.
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
435184, 514 18, 514 19, C12N 950, C12N 999, A61K 3800
Patent
active
059768584
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to novel cysteine protease inhibitors. The inhibitors are specific to cysteine proteases and do not inhibit serine, aspartyl or zinc protease.
BACKGROUND OF THE INVENTION
Cysteine or thiol proteases contain a cysteine residue at the active site responsible for proteolysis. Since cysteine proteases have been implicated in a number of diseases, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, and other parasite-borne infections, methods for selectively and irreversibly inactivating them provide opportunities for new drug candidates. See, for example, Meijers, M. H. M. et al., Agents Actions (1993), 39 (Special Conference Issue), C219; Machleidt, W. et al, Fibrinolysis (1992), 6 Suppl. 4, 125; Sloane, B. F. et al., Biomed. Biochim. Acta (1991), 50, 549; Duffy, M. J., Clin. Exp. Metastasis (1992), 10, 145; Rosenthal, P. J., Wollish, W. S., Palmer, J. T., Rasnick, D., J. Clin. Investigations (1991), 88, 1467; Baricos, W. H. et al, Arch. Biochem. Biophys. (1991), 288, 468; Thornberry, N. A. et al., Nature (1992), 356, 768.
Low molecular weight inhibitors of cysteine proteases have been described by Rich, Proteinase Inhibitors (Chapter 4, "Inhibitors of Cysteine Proteinases"), Elsevier Science Publishers (1986). Such inhibitors include peptide aldehydes, which form hemithioacetals with the cysteine of the protease active site. The disadvantage of aldehydes is their in vivo and chemical instabilities.
Aldehydes have been transformed into .alpha.,.beta.-unsaturated esters and sulfones by means of the Wadsworth-Emmons-Horner modification of the Wittig reaction (Wadsworth, W. S. and Emmons, W. D. (J. Am. Chem. Soc. (1961), 83, 1733: Equation 1).
Equation 1
##STR1## where R=alkyl, aryl, etc. EWG=COOEt, SO.sub.2 Me, etc.
.alpha.,.beta.-unsaturated esters (Hanzlik et al., J. Med. Chem., 27(6):711-712 (1984), Thompson et al., J. Med. Chem. 29:104-111 (1986), Liu et al., J. Med. Chem., 35(6):1067 (1992)) and an .alpha.,.beta.-unsaturated sulfones (Thompson et al., supra, Liu et al., supra) were made using this method and tested as inhibitors of two cysteine proteases, papain and dipeptidyl amino-peptidase I (also called cathepsin C). However, the inhibition of papain by these .alpha.,.beta.-unsaturated compounds showed poor inhibition, evidenced by second order rate constants from less than 1 M.sup.-1 sec.sup.-1 to less than 70 M.sup.-1 sec.sup.-1 for the .alpha.,.beta.-unsaturated esters, and from less than 20 M.sup.-1 sec.sup.-1 to less than 60 M.sup.-1 sec.sup.-1 for the sulfone.
In addition, this chemistry has not been demonstrated with derivatives of .alpha.-amino acids other than those corresponding to glycine, or in the case of the ester, phenylalanine. Thus the chirality of these compounds is non-existent for the glycine derivatives and unclear for the phenylalanine derivatives. This is significant since inhibition of an enzyme generally requires a chiral compound.
Additional methods for selectively and irreversibly inhibiting cysteine proteases have relied upon alkylation by peptide .alpha.-fluoromethyl ketones (Rasnick, D., Anal. Biochem. (1985), 149, 416), diazomethylketones (Kirschke, H., Shaw, E. Biochem. Biphys. Res. Commun. (1981), 101, 454), acyloxymethyl ketones (Krantz, A. et al., Biochemistry, (1991), 30, 4678; Krantz, A. et al., U.S. Pat. No. 5,055,451, issued Oct. 8, 1991), and ketosulfonium salts (Walker, B., Shaw, E., Fed. Proc. Fed. Am. Soc. Exp. Biol., (1985), 44, 1433). The proposed mechanism of inactivation relies upon irreversible inactivation of the active site thiol group via alkylation, as depicted in Equation 2.
Equation 2
##STR2## where PG=protecting group
Other families of cysteine protease inhibitors include epoxysuccinyl peptides, including E-64 and its analogs (Hanada, K. et al., Agric. Biol. Chem (1978), 42, 523; Sumiya, S. et al., Chem. Pharm. Bull. ((1992), 40, 299 Gour-Salin, B. J. et al., J. Med. Chem., (1993), 36, 720), .alpha.-dicarbonyl compounds, reviewed by Mehdi, S., Bio
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Klaus Jeffrey Lee
Palmer James T.
Rasnick David
Arris Pharmaceuticals
Brezner David J.
Silva Robin M.
Weber Jon P.
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