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

A series of butynyloxyphenyl beta-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-alpha production.

Sulfonate ester hydroxamic acids as potent and selective inhibitors of TACE enzyme.

Sulfonamide hydroxamate derivatives of anthranilic acids are known to be potent inhibitors of cell-free TACE enzyme. However, compounds of this structural class with both high potency and high selectivity for TACE over matrix metalloproteinases (MMPs) are uncommon. Replacement of the sulfonamide functionality with an isosteric sulfonate ester has resulted in a series of sulfonate ester hydroxamates, 2a-e, with excellent activity against TACE and excellent selectivity over MMP-1 and MMP-13.

Benzodiazepine inhibitors of the MMPs and TACE. Part 2.

A series of benzodiazepine MMP/TACE inhibitors bearing polar moieties has been synthesized in an effort to optimize inhibitory activity against LPS-stimulated TNF production in human monocytes and oral activity in a murine LPS model.