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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Aug 13; Vol. 52 (15), pp. 4757-73. - Publication Year :
- 2009
-
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.
- Subjects :
- ADAM Proteins chemistry
ADAM17 Protein
Cartilage metabolism
Hydroxamic Acids pharmacology
Hydroxamic Acids therapeutic use
Matrix Metalloproteinase 1 chemistry
Matrix Metalloproteinase 13 chemistry
Matrix Metalloproteinase 14 chemistry
Models, Molecular
Protease Inhibitors pharmacology
Protease Inhibitors therapeutic use
Structure-Activity Relationship
Drug Design
Hydroxamic Acids chemical synthesis
Matrix Metalloproteinase Inhibitors
Osteoarthritis drug therapy
Protease Inhibitors chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19606871
- Full Text :
- https://doi.org/10.1021/jm900261f