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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.

SUBMITTER: Kim IH 

PROVIDER: S-EPMC3517215 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Structure-activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase.

Kim In-Hae IH   Park Yong-Kyu YK   Hammock Bruce D BD   Nishi Kosuke K  

Journal of medicinal chemistry 20110221 6


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 pot  ...[more]

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