Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement.
4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.
Shen
Hong C
HC
Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065-0900, USA. hong_shen@merck.com
Ding
Fa-Xiang
FX
Wang
Siyi
S
Deng
Qiaolin
Q
Zhang
Xiaoping
X
Chen
Yuli
Y
Zhou
Gaochao
G
Xu
Suoyu
S
Chen
Hsuan-Shen
HS
Tong
Xinchun
X
Tong
Vincent
V
Mitra
Kaushik
K
Kumar
Sanjeev
S
Tsai
Christine
C
Stevenson
Andra S
AS
Pai
Lee-Yuh
LY
Alonso-Galicia
Magdalena
M
Chen
Xiaoli
X
Soisson
Stephen M
SM
Roy
Sophie
S
Zhang
Bei
B
Tata
James R
JR
Berger
Joel P
JP
Colletti
Steven L
SL
D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D008968:Molecular Conformation; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D015777:Eicosanoids; D004852:Epoxy Compounds; D007473:Ion Channels; D010880:Piperidines; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases