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Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds.

ABSTRACT: Matrix metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to the discovery of MMP-13 inhibitors 20 and 24 which are more selective than 4 against other MMPs. Compound 20 is also approximately fivefold more potent as an MMP-13 inhibitor than the original HTS-derived lead compound 4.

SUBMITTER: Roth J

PROVIDER: S-EPMC3210410 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds.

Roth Joshua J Minond Dmitriy D Darout Etzer E Liu Qin Q Lauer Janelle J Hodder Peter P Fields Gregg B GB Roush William R WR

Bioorganic & medicinal chemistry letters 20110922 23

Matrix metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to ...[more]

PMID: 22018790

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