title: Structure-based optimization of cyclopropyl urea derivatives as potent soluble epoxide hydrolase inhibitors for potential decrease of renal injury without hypotensive action.
abstract: Epoxyeicosatrienoic acids (EETs) are known to have beneficial pharmacological effects on various cardiovascular events. However, EETs are biologically metabolized by soluble epoxide hydrolase (sEH) to less active metabolites. In our search for potent sEH inhibitors, we optimized a series of cyclopropyl urea derivatives and identified compound 38 as a potent sEH inhibitor with minimal CYP inhibition and good oral absorption in rats. Administration of 38 to DOCA-salt rats suppressed urinary albumin and MCP-1 excretion without affecting systolic blood pressure.
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Kentaro
authors: K
authors: Takai
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Tomoko
authors: T
authors: Nakajima
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Yosuke
authors: Y
authors: Takanashi
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan. Electronic address: toshihiko-sone@ds-pharma.co.jp.
authors: Toshihiko
authors: T
authors: Sone
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Tetsuro
authors: T
authors: Nariai
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Naoki
authors: N
authors: Chiyo
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Shogo
authors: S
authors: Nakatani
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Chihiro
authors: C
authors: Ishikawa
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Nobuyuki
authors: N
authors: Yamaguchi
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Katsuya
authors: K
authors: Fujita
authors: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Kazuto
authors: K
authors: Yamada
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D007022:Hypotension / Q000188:drug therapy*; D051381:Rats; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D004852:Epoxy Compounds; D014508:Urea; D004851:Epoxide Hydrolases
keywords: Cyclopropyl urea; DOCA-salt rat; Epoxyeicosatrienoic acids; Inhibitors; Renal protection; Soluble epoxide hydrolase