1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: Structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain

Tristan E. Rose, Christophe Morisseau, Jun Yan Liu, Bora Inceoglu, Paul D. Jones, James R. Sanborn, Bruce D. Hammock

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97 Scopus citations

Abstract

1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl) piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl) urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.

Original languageEnglish (US)
Pages (from-to)7067-7075
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number19
DOIs
StatePublished - Oct 14 2010

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

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