Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-α converting enzyme (TACE) inhibitors

A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy) phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl) propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC50 of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14. (C) 2009 Elsevier Ltd. All rights reserved.