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Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage degradation and to halt the progression of OA. Herein, we report the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors possessing an arylsulfonamidic scaffold. Among these potential inhibitors, a very promising compound was discovered exhibiting nanomolar activity for MMP-13 and was highly selective for this enzyme compared to MMP-1, -14, and TACE. This compound acted as a slow-binding inhibitor of MMP-13 and was demonstrated to be effective in an in vitro collagen assay and in a model of cartilage degradation. Furthermore, a docking study was conducted for this compound in order to investigate its binding interactions with MMP-13 and the reasons for its selectivity toward MMP-13 versus other MMPs.

Original publication

DOI

10.1021/jm900261f

Type

Journal article

Journal

J Med Chem

Publication Date

13/08/2009

Volume

52

Pages

4757 - 4773

Keywords

ADAM Proteins, ADAM17 Protein, Cartilage, Drug Design, Hydroxamic Acids, Matrix Metalloproteinase 1, Matrix Metalloproteinase 13, Matrix Metalloproteinase 14, Matrix Metalloproteinase Inhibitors, Models, Molecular, Osteoarthritis, Protease Inhibitors, Structure-Activity Relationship