Structure−Activity Relationships of Cycloalkylamide Derivatives as Inhibitors of the Soluble Epoxide Hydrolase
- 21 February 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 54 (6), 1752-1761
- https://doi.org/10.1021/jm101431v
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.Keywords
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