Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-α converting enzyme (TACE)

A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11–60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.

Graphical abstractWe have discovered novel hydantoins that are drug-like, non-hydroxamate inhibitors of the matrix metalloprotease TACE with nM potency. Synthesis and SAR of these inhibitors is described as well as their selectivity against other MMPs.Figure optionsDownload full-size imageDownload as PowerPoint slide