title: Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement.
abstract: 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.
authors: Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065-0900, USA. hong_shen@merck.com
authors: Hong C
authors: HC
authors: Shen
authors: Fa-Xiang
authors: FX
authors: Ding
authors: Siyi
authors: S
authors: Wang
authors: Qiaolin
authors: Q
authors: Deng
authors: Xiaoping
authors: X
authors: Zhang
authors: Yuli
authors: Y
authors: Chen
authors: Gaochao
authors: G
authors: Zhou
authors: Suoyu
authors: S
authors: Xu
authors: Hsuan-Shen
authors: HS
authors: Chen
authors: Xinchun
authors: X
authors: Tong
authors: Vincent
authors: V
authors: Tong
authors: Kaushik
authors: K
authors: Mitra
authors: Sanjeev
authors: S
authors: Kumar
authors: Christine
authors: C
authors: Tsai
authors: Andra S
authors: AS
authors: Stevenson
authors: Lee-Yuh
authors: LY
authors: Pai
authors: Magdalena
authors: M
authors: Alonso-Galicia
authors: Xiaoli
authors: X
authors: Chen
authors: Stephen M
authors: SM
authors: Soisson
authors: Sophie
authors: S
authors: Roy
authors: Bei
authors: B
authors: Zhang
authors: James R
authors: JR
authors: Tata
authors: Joel P
authors: JP
authors: Berger
authors: Steven L
authors: SL
authors: Colletti
mesh_terms: 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
chemical_list: 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