Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro.
Publication Type:Journal Article
Source:J Med Chem, Volume 57, Issue 22, p.9598-611 (2014)
Keywords:Animals, Binding Sites, Cartilage, Cartilage, Articular, Cattle, Chemistry, Pharmaceutical, Collagen, Collagenases, Crystallography, X-Ray, Cytochrome P-450 Enzyme System, Drug Design, Humans, Hydrolysis, Inhibitory Concentration 50, Kinetics, Matrix Metalloproteinase 13, Matrix Metalloproteinase Inhibitors, Mice, Microsomes, Molecular Conformation, Osteoarthritis, Protein Binding, Protein Conformation, Rats, Structure-Activity Relationship
<p>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 1 (Q), 2 (Q1), and 3 (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 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 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.</p>