Design, synthesis and SAR investigation of thienosultam derivatives as ADAMTS-5 (aggrecanase-2) inhibitors

A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1′ pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability.