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

作者：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

来源：Journal of Medicinal Chemistry, 2009, 52(11): 3523-3538.

DOI：10.1021/jm801394m

The matrix metal loproteinase 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-alpha (TNF-alpha) 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 2417 for further development. Compound 2417 is a subnanomolar inhibitor of MMP-13 (IC(50) 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, 2417 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).

• 出版日期2009-6-11