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.
Guo
Zhuyan
Z
Department of Chemistry, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. zhuyan.guo@spcorp.com
Orth
Peter
P
Wong
Shing-Chun
SC
Lavey
Brian J
BJ
Shih
Neng-Yang
NY
Niu
Xiaoda
X
Lundell
Daniel J
DJ
Madison
Vincent
V
Kozlowski
Joseph A
JA
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
D002264:Carboxylic Acids; D006877:Hydroxamic Acids; D008024:Ligands; D013141:Spiro Compounds; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015032:Zinc