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J Med Chem. 2014 Nov 26;57(22):9598-611. doi: 10.1021/jm501284e. Epub 2014 Nov 11.

Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro.

Author information

1
Lead Identification Division, Translational Research Institute, ‡Department of Molecular Therapeutics, and §Department of Chemistry, Scripps Florida, The Scripps Research Institute , Jupiter, Florida 33458, United States.

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 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.

PMID:
25330343
PMCID:
PMC4255739
DOI:
10.1021/jm501284e
[Indexed for MEDLINE]
Free PMC Article

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