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

…, R Doti, J Doughty, J Fang, D Farley, J Fitt…

Index: Monovich, Lauren G.; Tommasi, Ruben A.; Fujimoto, Roger A.; Blancuzzi, Vincent; Clark, Kirk; Cornell, Wendy D.; Doti, Robert; Doughty, John; Fang, James; Farley, David; Fitt, John; Ganu, Vishwas; Goldberg, Ronald; Goldstein, Robert; Lavoie, Stacey; Kulathila, Raviraj; Macchia, William; Parker, David T.; Melton, Richard; O'Byrne, Elizabeth; Pastor, Gary; Pellas, Theodore; Quadros, Elizabeth; Reel, Noela; Roland, Dennis M.; Sakane, Yumi; Singh, Hem; Skiles, Jerry; Somers, Joseph; Toscano, Karen; Wigg, Andrew; Zhou, Siyuan; Zhu, Lijuan; Shieh, Wen-Chung; Xue, Song; McQuire, Leslie W. Journal of Medicinal Chemistry, 2009 , vol. 52, # 11 p. 3523 - 3538

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Citation Number: 39

Abstract

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) ...