Proteases regulate a broad spectrum of physiological functions by the specific processing ofproteins and peptides. Elevated levels of activeproteases can result in an array of physiological processes ultimately leading to disease states. Therefore, compounds designedto restore the naturalequilibrium of proteases present excellent opportunitiesfordrug candidates. Cysteine proteases, for example cathepsins B, L, and S, have been implicated in a number of diseases, including progressive cartilage and bone degradation associated with arthritis. 1 Inhibitors of these cathepsins have reduced inflammation andprevented joint destruc-tion in animal models of arthritis. 2 Recently, human cathepsin 02 has been found to be highly expressed in osteoclastoma tissue. 3 Cathepsins B and L have been linked to metastasis and invasionby cancer cells. 4 The calcium-associatedcysteine proteases calpains I and II have been associated with ischemia andhypoxia, 5 Alzheimer’s disease, 6 and cataracts. 7 Inhibition of the trypanosomal cysteine protease cruzain hasproven effective in models of Chagas’s disease. 8 Reversible inhibitors of cysteine proteases include peptide aldehydes, 9 nitriles, 10 and a-ketocarbonyl com-pounds. 11 Irreversible inhibitors includepeptide ha-lomethyl ketones, 12 diazomethyl ketones, 13 (acyloxy)-methyl ketones, 14 and ketomethylsulfonium salts, 15 believed to alkylatethe active site thiol by formal Sn2 displacement, eitherdirectly or through a proposed hemithioketal-episulfonium ionpathway. Other irreversible inhibitors include various epoxysuccinyl com-pounds, 16 whose oxiranes are opened through nucleo-philic attack bythe thiol.

Previous work by Hanzlik and co-workers17 demon-strated peptide Michael acceptors as inactivators of the plant protease papain, which displayed second-order rate constants of inactivation from 0.05 to 70 M’1 s’1. However, to serve as disease modifying agents, inhibi-tors must inactivatetarget enzymes sufficiently in vivo