Structure-based design of TACE selective inhibitors: Manipulations in the S1′–S3′ pocket

A series of β-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1′ group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-α production.

A series of β-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino P1′ group, was designed and synthesized. Of the compounds investigated, 22 has excellent in vitro potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-α production.Figure optionsDownload as PowerPoint slide