Design, Synthesis, and Biological Evaluation of Potent Thiazine- and Thiazepine-Based Matrix Metalloproteinase Inhibitors
文摘
The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrixmetalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitorswere discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potentseries of inhibitors was obtained by modification of the amino acid D-penicillamine. This aminoacid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramaticeffect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5awere potent, broad-spectrum inhibitors of the MMPs with IC50's against MMP-1 of 0.8 and 1.9nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitorswas established based on X-ray crystallography of the complex of stromelysin and 4a.