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

In Hae Kim, Yong Kyu Park, Bruce D. Hammock, Kosuke Nishi

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1752-1761
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number6
DOIs
StatePublished - Mar 24 2011

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Epoxide Hydrolases
Structure-Activity Relationship
Cycloparaffins
Amides
Tetrahydronaphthalenes
Hydrophobic and Hydrophilic Interactions
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase. / Kim, In Hae; Park, Yong Kyu; Hammock, Bruce D.; Nishi, Kosuke.

In: Journal of Medicinal Chemistry, Vol. 54, No. 6, 24.03.2011, p. 1752-1761.

Research output: Contribution to journalArticle

Kim, In Hae ; Park, Yong Kyu ; Hammock, Bruce D. ; Nishi, Kosuke. / Structure-activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 6. pp. 1752-1761.
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