N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.

Abstract

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.

DOI: 10.1021/jm900261f

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@article{Nuti2009NOisopropylSH, title={N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.}, author={Elisa Nuti and Francesca Casalini and Stanislava I Avramova and Salvatore Santamaria and Giovanni Cercignani and Luciana Marinelli and Valeria La Pietra and Ettore Novellino and Elisabetta Orlandini and Susanna Nencetti and Tiziano Tuccinardi and Adriano Martinelli and Ngee-Han Lim and Robert Visse and Hideaki Nagase and Armando Rossello}, journal={Journal of medicinal chemistry}, year={2009}, volume={52 15}, pages={4757-73} }