Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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

Journal of medicinal chemistry

Publication Date

08/2009

Volume

52

Pages

4757 - 4773

Addresses

Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.

Keywords

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