Discovery and SAR of hydantoin TACE inhibitors.
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.
Yu
Wensheng
W
Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. wensheng.yu@spcorp.com
Guo
Zhuyan
Z
Orth
Peter
P
Madison
Vincent
V
Chen
Lei
L
Dai
Chaoyang
C
Feltz
Robert J
RJ
Girijavallabhan
Vinay M
VM
Kim
Seong Heon
SH
Kozlowski
Joseph A
JA
Lavey
Brian J
BJ
Li
Dansu
D
Lundell
Daniel
D
Niu
Xiaoda
X
Piwinski
John J
JJ
Popovici-Muller
Janeta
J
Rizvi
Razia
R
Rosner
Kristin E
KE
Shankar
Bandarpalle B
BB
Shih
Neng-Yang
NY
Siddiqui
M Arshad
MA
Sun
Jing
J
Tong
Ling
L
Umland
Shelby
S
Wong
Michael K C
MK
Yang
De-yi
DY
Zhou
Guowei
G
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
D004791:Enzyme Inhibitors; D006827:Hydantoins; D051722:ADAM Proteins; D000072198:ADAM17 Protein