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, P. John Hart, William R. Roush, Gregg B. Fields, Peter S. Hodder, Dmitriy Minond

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17 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

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Spicer, T. P., Jiang, J., Taylor, A. B., Choi, J. Y., Hart, P. J., Roush, W. R., Fields, G. B., Hodder, P. S., & Minond, D. (2014). Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro. Journal of Medicinal Chemistry, 57(22), 9598-9611. https://doi.org/10.1021/jm501284e