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

Timothy P. Spicer, Jianwen Jiang, Alexander B. Taylor, Jun Yong Choi, Peter J Hart, William R. Roush, Gregg B. Fields, Peter S. Hodder, Dmitriy Minond

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 and z.ast; 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.

Original languageEnglish (US)
Pages (from-to)9598-9611
Number of pages14
JournalJournal of Medicinal Chemistry
Volume57
Issue number22
DOIs
StatePublished - Nov 26 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro'. Together they form a unique fingerprint.

Cite this