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

Authors: Kim, In-Hae; Park, Yong-Kyu; Hammock, Bruce D; Nishi, Kosuke

Published In J Med Chem, (2011 Mar 24)

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.

PubMed ID: 21338111

MeSH Terms: Adamantane/chemical synthesis; Adamantane/chemistry; Amides/chemical synthesis*; Amides/chemistry; Cyclohexanes/chemical synthesis; Cyclohexanes/chemistry; Cyclopentanes/chemical synthesis; Cyclopentanes/chemistry; Cyclopropanes/chemical synthesis; Cyclopropanes/chemistry; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/chemistry; Humans; Naphthalenes/chemical synthesis; Naphthalenes/chemistry; Solubility; Stereoisomerism; Structure-Activity Relationship