title: Discovery of 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating of chronic kidney diseases.
abstract: We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity and bioavailability. When administered orally at 30 mg/kg, 19 lowered serum creatinine in a rat model of anti-glomerular basement membrane glomerulonephritis but 2,8-diazaspiro[4.5]decane-based trisubstituted ureas did not. These results suggest that 19 is an orally active drug candidate for treating chronic kidney diseases.
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan; Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan. Electronic address: Yuko_Kato@nts.toray.co.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fuchi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nakadera
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Higashi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kigoshi
mesh_terms: D000284:Administration, Oral; D000473:Alkanes / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000201:enzymology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000473:Alkanes; D014508:Urea; D004851:Epoxide Hydrolases; C022884:undecane
keywords: Anti-GBM glomerulonephritis rat model; Chronic kidney diseases; Spirocyclic diamine; Urea; sEH inhibitor