Design, Synthesis, and Biological Evaluation of Potent Thiazine- and Thiazepine-Based Matrix Metalloproteinase Inhibitors

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• 作者：Neil G. Almstead ; Rimma S. Bradley ; Stanislaw Pikul ; Biswanath De ; Michael G. Natchus ; Yetunde O. Taiwo ; Fei Gu ; Lisa E. Williams ; Barbara A. Hynd ; Michael J. Janusz ; C. Michelle Dunaway ; and Glen E.
• 刊名：Journal of Medicinal Chemistry
• 出版年：1999
• 出版时间：November 4, 1999
• 年：1999
• 卷：42
• 期：22
• 页码：4547 - 4562
• 全文大小：507K
• 年卷期：v.42,no.22(November 4, 1999)
• ISSN：1520-4804

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.