Matrix metalloproteinase inhibitors

Patent Summary

Phosphinic acid-containing peptide derivatives are disclosed as inhibitors of proteases, especially stromelysin and gelatinase. These are useful for treating both rheumatoid and osteoarthritis. In addition, these enzymes are implicated in certain tumour metastases and coronary thrombosis associated with atherosclerotic plaque rupture. They have application as birth control agents.

Enzyme activities were determined with a fluorogenic peptide substrate and stromelysin, collagenase and gelatinase obtained from human fibroblasts. K_i values are given for seven peptides. The compounds had little activity against collagenase but K; values of 1-50 nM against stromelysin and gelatinase, were determined. The specified compound had Ki values of 6.1 and 2.6 nM, respectively.

The preparation of the peptide derivatives is illustrated by three schemes and seven examples. Fifty-nine compounds are disclosed in tables. Eight compounds are specifically claimed, including 2-[[hydroxyl[1(R)-[N-(N-acetyl-L-prolyl-L-alanyl)aminol-ethyllphosphiny-1]-methyl]-4-phenylbutanoyl-L-leucyl-N-phenylamide.