Discovery of Potent, Selective, and Orally Active Carboxylic Acid Based Inhibitors of Matrix Metalloproteinase-13

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• 作者：Lauren G. Monovich ; Ruben A. Tommasi ; Roger A. Fujimoto ; Vincent Blancuzzi ; Kirk Clark ; Wendy D. Cornell ; Robert Doti ; John Doughty ; James Fang ; David Farley ; John Fitt ; Vishwas Ganu ; Ronald Goldberg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 11, 2009
• 年：2009
• 卷：52
• 期：11
• 页码：3523-3538
• 全文大小：350K
• 年卷期：v.52,no.11(June 11, 2009)
• ISSN：1520-4804

文摘

The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-α (TNF-α) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC₅₀ value 0.5 nM and K_i of 0.19 nM) having no activity against MMP-1 or TACE (IC₅₀ of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).