title: Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors.
abstract: We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values).
authors: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan. Electronic address: kentaro-takai@ds-pharma.co.jp.
authors: Kentaro
authors: K
authors: Takai
authors: Drug Research Division, Sumitomo Dainippon 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, Sumitomo Dainippon 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, Sumitomo Dainippon 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, Sumitomo Dainippon 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, Sumitomo Dainippon 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, Sumitomo Dainippon Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Akihisa
authors: A
authors: Ikeno
authors: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Setsuko
authors: S
authors: Yamamoto
authors: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 3-1-98 Kasugade-naka, Konohana-ku, Osaka-city, Osaka 554-0022, Japan.
authors: Toshihiko
authors: T
authors: Sone
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism
chemical_list: D003521:Cyclopropanes; D014508:Urea; C030797:cyclopropane; D004851:Epoxide Hydrolases
keywords: Conformational regulation; Epoxyeicosatrienoic acids; Inhibitor; Soluble epoxide hydrolase; Three substituted cyclopropane