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

Research output: Contribution to journalArticle

95 Citations (Scopus)

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

Fingerprint

Epoxide Hydrolases
Structure-Activity Relationship
Urea
Pharmacokinetics
Pain
Adamantane
Carrageenan
Hyperalgesia
Morphine
Area Under Curve
Oral Administration

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

Cite this

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

In: Journal of Medicinal Chemistry, Vol. 53, No. 19, 14.10.2010, p. 7067-7075.

Research output: Contribution to journalArticle

Rose, Tristan E. ; Morisseau, Christophe ; Liu, Jun Yan ; Inceoglu, Bora ; Jones, Paul D. ; Sanborn, James R. ; Hammock, Bruce D. / 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. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 19. pp. 7067-7075.
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