Biaryl substituted hydantoin compounds as TACE inhibitors.
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Yu
Wensheng
W
Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. wensheng.yu@merck.com
Tong
Ling
L
Kim
Seong Heon
SH
Wong
Michael K C
MK
Chen
Lei
L
Yang
De-Yi
DY
Shankar
Bandarpalle B
BB
Lavey
Brian J
BJ
Zhou
Guowei
G
Kosinski
Aneta
A
Rizvi
Razia
R
Li
Dansu
D
Feltz
Robert J
RJ
Piwinski
John J
JJ
Rosner
Kristin E
KE
Shih
Neng-Yang
NY
Siddiqui
M Arshad
MA
Guo
Zhuyan
Z
Orth
Peter
P
Shah
Himanshu
H
Sun
Jing
J
Umland
Shelby
S
Lundell
Daniel J
DJ
Niu
Xiaoda
X
Kozlowski
Joseph A
JA
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat