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

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 Ki 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,...