title: Structure-activity relationships of substituted oxyoxalamides as inhibitors of the human soluble epoxide hydrolase.
abstract: We explored both structure-activity relationships among substituted oxyoxalamides used as the primary pharmacophore of inhibitors of the human sEH and as a secondary pharmacophore to improve water solubility of inhibitors. When the oxyoxalamide function was modified with a variety of alkyls or substituted alkyls, compound 6 with a 2-adamantyl group and a benzyl group was found to be a potent sEH inhibitor, suggesting that the substituted oxyoxalamide function is a promising primary pharmacophore for the human sEH, and compound 6 can be a novel lead structure for the development of further improved oxyoxalamide or other related derivatives. In addition, introduction of substituted oxyoxalamide to inhibitors with an amide or urea primary pharmacophore produced significant improvements in inhibition potency and water solubility. In particular, the N,N,O-trimethyloxyoxalamide group in amide or urea inhibitors (26 and 31) was most effective among those tested for both inhibition and solubility. The results indicate that substituted oxyoxalamide function incorporated into amide or urea inhibitors is a useful secondary pharmacophore, and the resulting structures will be an important basis for the development of bioavailable sEH inhibitors.
authors.affiliation: Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry, Hyundai Pharm Co., Ltd, Suwon, Gyonggi 443-270, Republic of Korea.
authors.forename: In-Hee
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nishiwaki
authors.affiliation: Department of Entomology & UCD Comprehensive Cancer Center, University of California Davis, One Shields Ave, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan. Electronic address: knishi@agr.ehime-u.ac.jp.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nishi
mesh_terms: D000577:Amides / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D010072:Oxamic Acid / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D014508:Urea; D004851:Epoxide Hydrolases; D010072:Oxamic Acid
keywords: 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide; 4-dimethylaminopyridine; CMNPC; DMAP; DMF; EDCI; EETs; Human soluble epoxide hydrolase; Inhibitors; N,N-dimethylformamide; Substituted oxyoxalamides; cyano-(2-methoxynaphthalen-6-yl)-methyl trans-(3-phenyl-oxyran-2-yl)-methyl carbonate; epoxyeicosatrienoic acids; sEH; soluble epoxide hydrolase