Design and synthesis of butynyloxyphenyl β-sulfone piperidine hydroxamates as TACE inhibitors

A series of butynyloxyphenyl β-sulfone piperidine hydroxamate TACE inhibitors was designed and synthesized. The resulting structure–activity relationship and MMP selectivity of the series were examined. Of the compounds investigated, 17s has excellent in vitro potency against isolated TACE enzyme, shows good selectivity over MMP-1, -2, -7, -8, -9, -13, and -14, and oral activity in an in vivo mouse model of TNF-α production.