Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors

We have discovered nanomolar inhibitors of TNF-α convertase (TACE) comprised of a novel spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. X-ray crystal structures and computer models of selected compounds binding to TACE explain the observed SAR. We report the first TACE X-ray crystal structure for an inhibitor with a carboxylate zinc ligand.

Graphical abstractA novel class of TACE inhibitors having nanomolar potency is described. The compounds have a spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. We report the first X-ray crystal structure for a TACE inhibitor with a carboxylate Zn ligand.The compounds have a spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. We report the first X-ray crystal structure for a TACE inhibitor with a carboxylate Zn ligand.Figure optionsDownload full-size imageDownload as PowerPoint slide