Discovery and SAR of hydantoin TACE inhibitors

We disclose inhibitors of TNF-α converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

Graphical abstractA novel series of hydantoin TACE inhibitors is disclosed. The initial design and SAR optimization of the series, as well as accompanying X-ray structural and modeling considerations, are described.Figure optionsDownload full-size imageDownload as PowerPoint slide