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

Abstract

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–activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds <b>1</b> (Q), <b>2</b> (Q1), and <b>3</b> (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 <b>2</b> in the MMP-13 S₁′ subsite and in an S₁/S₂* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds <b>1</b>, <b>2</b>, and <b>3</b> 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–drug interactions in humans