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.
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Authors | 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 15
Pg. 4757-73
(Aug 13 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19606871
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Hydroxamic Acids
- Matrix Metalloproteinase Inhibitors
- Protease Inhibitors
- ADAM Proteins
- Matrix Metalloproteinase 13
- Matrix Metalloproteinase 1
- Matrix Metalloproteinase 14
- ADAM17 Protein
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Topics |
- ADAM Proteins
(chemistry)
- ADAM17 Protein
- Cartilage
(metabolism)
- Drug Design
- Hydroxamic Acids
(chemical synthesis, pharmacology, therapeutic use)
- Matrix Metalloproteinase 1
(chemistry)
- Matrix Metalloproteinase 13
(chemistry)
- Matrix Metalloproteinase 14
(chemistry)
- Matrix Metalloproteinase Inhibitors
- Models, Molecular
- Osteoarthritis
(drug therapy)
- Protease Inhibitors
(chemical synthesis, pharmacology, therapeutic use)
- Structure-Activity Relationship
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