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EnglishMatrix 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 ofMMP-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.
| Autori interni: | ||
| Autori: | E. NUTI; F. CASALINI; S. I. AVRAMOVA; S. SANTAMARIA; CERCIGNANI G; L. MARINELLI; V. LA PIETRA; E. NOVELLINO; E. ORLANDINI; S. NENCETTI; T. TUCCINARDI; A. MARTINELLI; N.H. LIM; R. VISSE; H. NAGASE; A. ROSSELLO | |
| Titolo: | N-O-Isopropyl Sulfonamido-Based Hydroxamates: Design, Synthesis and Biological Evaluation of Selective Matrix Metalloproteinase-13 Inhibitors as Potential Therapeutic Agents for Osteoarthritis | |
| Anno del prodotto: | 2009 | |
| Digital Object Identifier (DOI): | 10.1021/jm900261f | |
| Appare nelle tipologie: | 1.1 Articolo in rivista |
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