Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors

We have discovered nanomolar inhibitors of TNF-alpha 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. (C) 2008 Elsevier Ltd. All rights reserved.