title: Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.
abstract: Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.
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: Siyi
authors.initials: S
authors.lastname: Wang
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: Kaushik
authors.initials: K
authors.lastname: Mitra
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
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: Xiaoli
authors.initials: X
authors.lastname: Chen
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
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: D000588:Amines / Q000737:chemistry*; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051381:Rats; D011918:Rats, Inbred SHR; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: D000588:Amines; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D014508:Urea; D004851:Epoxide Hydrolases