1. Metabolism resistant isothiazolone inhibitors of cartilage breakdown
- Author
-
Stephen W. Wright, Douglas Guy Batt, M. A. Pratta, Joseph J. Petraitis, Ronald L. Magolda, E. C. Arner, Susan R. Sherk, John V. Giannaras, Donald Joseph-Phillip Pinto, Orwat Michael James, Ronald L. Corbett, Bruce Freimark, Jean M. Williams, Susan V. Di Meo, and Herman F. Stampfli
- Subjects
Pyridines ,Indomethacin ,Clinical Biochemistry ,Pharmaceutical Science ,Matrix metalloproteinase ,Organ culture ,Biochemistry ,Structure-Activity Relationship ,Naproxen ,Organ Culture Techniques ,Reductive metabolism ,Microsomes ,Drug Discovery ,Nasal septum ,medicine ,Animals ,Molecular Biology ,Nasal Septum ,Chemistry ,Cartilage ,Organic Chemistry ,Metalloendopeptidases ,Metabolism ,Thiazoles ,medicine.anatomical_structure ,Microsome ,Pyrazoles ,Molecular Medicine ,Cattle ,Matrix Metalloproteinase 3 ,Proteoglycans ,Oxidation-Reduction ,Interleukin-1 - Abstract
A series of 2-(arylmethyl)pyridoisothiazolones is reported that inhibit the IL-1 β induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, non-peptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.
- Published
- 1995