Effects of adamantane alterations on soluble epoxide hydrolase inhibition potency, physical properties and metabolic stability

Vladimir Burmistrov, Christophe Morisseau, Todd R. Harris, Gennady Butov, Bruce D. Hammock

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds.

Original languageEnglish (US)
Pages (from-to)510-527
Number of pages18
JournalBioorganic Chemistry
Volume76
DOIs
StatePublished - Feb 1 2018

Keywords

  • Adamantane
  • Inhibitor
  • Isocyanate
  • Soluble epoxide hydrolase
  • Urea

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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