Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors

The synthesis and enzyme inhibition data for a series of thiazine- and thia zepine-based matrix metalloproteinase (MMP) inhibitors are described. The t hiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inh ibitors was obtained by modification of the amino acid D-penicillamine. Thi s amino acid provides a gem-dimethyl group on the thiazine or thiazepine ri ng which has a dramatic effect on the in vitro potency of this series. In p articular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum in hibitors of the MMPs with IC50's against MMP-1 of 0.8 and 1.9 nM, respectiv ely. The binding mode of this novel thiazepine-based series of MMP inhibito rs was established based on X-ray crystallography of the complex of stromel ysin and 4a.