MMP inhibitors are partially protective against cartilage and subchondral bone damage induced by iodoacetate. These results support an important role for MMPs in mediating the joint damage in this model of arthritis.

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of activation suggests that N2 loss from 4 to give 5 is not a concerted process and probably involves a rate-determining ligand rearrangement (perhaps ring expansion with formation of a Zr-0 bond) before N2 extrusion occurs, 5 is reactive toward a number of other small molecules, and elaboration of this reaction chemistry will be the topic of a future publication.Acknowledgment. Financial support from the National Science Foundation (CHE-8818607) and an Alfred P. Sloan Foundation Research Fellowship (1989-1991 is sincerely appreciated by G.L.H. A summer fellowship under the N.S.F. Research Experiences for Undergraduates Program (NSF 8713014) is gratefully acknowledged by C.D.S. The NMR facilities were supported in part through the University of Chicago Cancer Center Grant (NIH-CA-14599).Supplementary Material Available: Experimental, spectroscopic ( , l3C NMR, and IR), analytical, and crystallographic details and tables of atomic coordinates, bond angles and distances,

The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.

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