title: Structure-activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase.
abstract: Structure-activity relationships of cycloalkylamide compounds as inhibitors of human sEH were investigated. When the left side of amide function was modified by a variety of cycloalkanes, at least a C6 like cyclohexane was necessary to yield reasonable inhibition potency on the target enzyme. In compounds with a smaller cycloalkane or with a polar group on the left side of amide function, no inhibition was observed. On the other hand, increased hydrophobicity dramatically improved inhibition potency. Especially, a tetrahydronaphthalene (20) effectively increased the potency. When a series of alkyl or aryl derivatives of cycloalkylamide were investigated to continuously optimize the right side of the amide pharmacophore, a benzyl moiety functionalized with a polar group produced highly potent inhibition. A nonsubstituted benzyl, alkyl, aryl, or biaryl structure present on the right side of the cycloalkylamide function induced a big decrease in inhibition potency. Also, the resulting potent cycloalkylamide (32) showed reasonable physical properties.
authors.affiliation: Industry and Academic Cooperation Laboratory for Drug Development, Mokpo National University, Muan, Jeonnam 534-729, Republic of Korea.
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Park
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nishi
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D003510:Cyclohexanes; D003517:Cyclopentanes; D003521:Cyclopropanes; D009281:Naphthalenes; D004851:Epoxide Hydrolases; D000218:Adamantane