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

• Published in: Journal of medicinal chemistry Vol. 42; no. 22; pp. 4547 - 4562
• Main Authors: Almstead, Neil G, Bradley, Rimma S, Pikul, Stanislaw, De, Biswanath, Natchus, Michael G, Taiwo, Yetunde O, Gu, Fei, Williams, Lisa E, Hynd, Barbara A, Janusz, Michael J, Dunaway, C. Michelle, Mieling, Glen E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 04-11-1999
• Subjects: Biological and medical sciences; Crystallography, X-Ray; Cyclic S-Oxides - chemical synthesis; Cyclic S-Oxides - chemistry; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Structure-Activity Relationship; Thiazepines - chemical synthesis; Thiazepines - chemistry; Thiazines - chemical synthesis; Thiazines - chemistry; Sulfur nitrogen heterocycle; Ring size; Sulfonamide; Sulfone; Enzyme; Hydroxamic acid; Enzyme inhibitor; Metalloendopeptidases; In vitro; Peptidases; Geminal compound; Structure activity relation; Six membered ring; Hydrolases; Chemical synthesis; Seven membered ring
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990330y

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 IC50'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.