Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase

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

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore.

Original languageEnglish (US)
Pages (from-to)7199-7210
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2015

Keywords

  • Amidephosphonate derivatives
  • Inhibitors
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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