title: Discovery and SAR of hydantoin TACE inhibitors.
abstract: We disclose inhibitors of TNF-alpha 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. wensheng.yu@spcorp.com
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yu
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Dai
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Feltz
authors.forename: Vinay M
authors.initials: VM
authors.lastname: Girijavallabhan
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Kim
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lavey
authors.forename: Dansu
authors.initials: D
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Niu
authors.forename: John J
authors.initials: JJ
authors.lastname: Piwinski
authors.forename: Janeta
authors.initials: J
authors.lastname: Popovici-Muller
authors.forename: Razia
authors.initials: R
authors.lastname: Rizvi
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Rosner
authors.forename: Bandarpalle B
authors.initials: BB
authors.lastname: Shankar
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: M Arshad
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Ling
authors.initials: L
authors.lastname: Tong
authors.forename: Shelby
authors.initials: S
authors.lastname: Umland
authors.forename: Michael K C
authors.initials: MK
authors.lastname: Wong
authors.forename: De-yi
authors.initials: DY
authors.lastname: Yang
authors.forename: Guowei
authors.initials: G
authors.lastname: Zhou
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D006827:Hydantoins; D051722:ADAM Proteins; D000072198:ADAM17 Protein