Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

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• 作者：Timothy P. Spicer ; Jianwen Jiang ; Alexander B. Taylor ; Jun Yong Choi ; P. John Hart ; William R. Roush ; Gregg B. Fields ; Peter S. Hodder ; Dmitriy Minond
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：57
• 期：22
• 页码：9598-9611
• 全文大小：743K
• ISSN：1520-4804

文摘

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure鈥揳ctivity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S₁鈥?subsite and in an S₁/S₂* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug鈥揹rug interactions in humans.