Heterocycle-based MMP inhibitors with P2 ' substituents

Potent and selective inhibition of matrix metalloproteinases was demonstrat ed fur a series of sulfonamide-based hydroxamic acids. The design of the he terocyclic sulfonamides incorporates a six- or seven-member central ring wi th a P2 ' substituent that can be modified. Binding interactions of this su bstituent at the S2 ' site are believed to contribute to high inhibitory po tency against stromelysin, collagenase-3 and gelatinases A and B, and to pr ovide selectivity against collagenase-1 and matrilysin. An X-ray structure of a stromelysin-inhibitor complex was obtained to provide insights into th e SAR and selectivity trends observed for the series. (C) 2001 Elsevier Sci ence Ltd. All rights reserved.