title: Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. zhuyan.guo@spcorp.com
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Shing-Chun
authors.initials: SC
authors.lastname: Wong
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lavey
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Niu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lundell
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc
chemical_list: D002264:Carboxylic Acids; D006877:Hydroxamic Acids; D008024:Ligands; D013141:Spiro Compounds; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015032:Zinc