title: Discovery of 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating hypertension.
abstract: We identified 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating hypertension. Docking studies using human and murine sEH X-ray crystal structures revealed steric hindrance around the side chain of Phe406 of murine sEH. The trifluoromethyl moiety (11) was replaced with a trifluoromethoxy moiety (12) to prevent steric clash, and improved murine sEH inhibitory activity was observed. The oral administration of 12, 20, and 37 at a dose of 30mg/kg reduced blood pressure in spontaneously hypertensive rat, but had little effect on blood pressure in normotensive rat.
authors.affiliation: Toray Industries Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Yuko_Kato@nts.toray.co.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kato
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fuchi
authors.forename: Hajime
authors.initials: H
authors.lastname: Saburi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Ayano
authors.initials: A
authors.lastname: Watanabe
authors.forename: Mai
authors.initials: M
authors.lastname: Yagi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nakadera
authors.forename: Eriko
authors.initials: E
authors.lastname: Higashi
authors.forename: Masateru
authors.initials: M
authors.lastname: Yamada
authors.forename: Takumi
authors.initials: T
authors.lastname: Aoki
mesh_terms: D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology; D062105:Molecular Docking Simulation; D051381:Rats; D011918:Rats, Inbred SHR; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000473:Alkanes; D000959:Antihypertensive Agents; D014508:Urea; D004851:Epoxide Hydrolases; C012867:decane
keywords: Hypertension; Mean blood pressure; Spirocyclic diamine; Spontaneously hypertensive rat; Urea; sEH inhibitor