title: Discovery of 3,3-disubstituted piperidine-derived trisubstituted ureas as highly potent soluble epoxide hydrolase inhibitors.
abstract: 3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. hong_shen@merck.com
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.forename: Suoyu
authors.initials: S
authors.lastname: Xu
authors.forename: Hsuan-Shen
authors.initials: HS
authors.lastname: Chen
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Vincent
authors.initials: V
authors.lastname: Tong
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuli
authors.initials: Y
authors.lastname: Chen
authors.forename: Gaochao
authors.initials: G
authors.lastname: Zhou
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D010880:Piperidines; C032727:piperidine; D014508:Urea; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid