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N-O-Isopropyl Sulfonamido-Based Hydroxamates: Design, Synthesis and Biological Evaluation of Selective Matrix Metalloproteinase-13 Inhibitors as Potential Therapeutic Agents for Osteoarthritis

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posted on 2009-08-13, 00:00 authored by Elisa Nuti, Francesca Casalini, Stanislava I. Avramova, Salvatore Santamaria, Giovanni Cercignani, Luciana Marinelli, Valeria La Pietra, Ettore Novellino, Elisabetta Orlandini, Susanna Nencetti, Tiziano Tuccinardi, Adriano Martinelli, Ngee-Han Lim, Robert Visse, Hideaki Nagase, Armando Rossello
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.