Metabolism resistant isothiazolone inhibitors of cartilage breakdown

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. A series of pyridoisothiazolones ( 1) is reported that inhibit the IL-1β induced breakdown of cartilage in an organ culture assay. Compounds 1 are resistant to reductive metabolism and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix matalloproteinase.