Reverse hydroxamate derivatives as matrix metalloprotease inhibitors, metalloprotease inhibitors, and TNF alpha inhibitors.

摘要

A family of compounds having general structural formula (I) wherein W is a reverse hydroxamic acid group (a); R5 is hydrogen or lower alkyl; R6 is (b); where Z1 is heteroarylene; preferably: R1 is methyl, ethyl, isopropyl, n-propyl or 3,3,3-trifluoro-n-propyl; R2 is isobutyl or sec-butyl; R3 is hydrogen; R4 is tert-butyl, sec-butyl, 1-methoxy-1-ethyl or 2-(2-pyridylcarbonylamino)-1-ethyl; R5 is hydrogen; and R6 is 2-thiazolyl or 2-pyridyl. Such compounds show potent inhibition of MMP's, cell-free TNF convertase enzyme and TNF release from cells, and in some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases.