HETEROARYL-FUSED 2-PHENYLISOTHIAZOLONE INHIBITORS OF CARTILAGE BREAKDOWN

The synthesis, biological evaluation, and structure-activity relations hips of a series of N-phenyl heteroaryl-fused isothiazolones are descr ibed. These isothiazolones have been shown to exhibit potent, dose-dep endent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This effect is likely due to inhibition of MMP activation and a consequent reduction in MMP activity followin g IL-1 beta stimulation. Thus these compounds potentially represent si mple, non-peptidic disease-modifying agents for the treatment of arthr itic diseases. To examine the effects of structure on in vitro activit y, three general features of the molecules were varied, substituents o n the pendant N-phenyl group, the position of ring fusion to the isoth iazolone, and substituents on the fused ring peri to the isothiazolone sulfur.