Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase

Sung Hee Hwang, Karen M. Wagner, Christophe Morisseau, Jun Yan Liu, Hua Dong, Aaron T. Wecksler, Bruce D. Hammock

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.

Original languageEnglish (US)
Pages (from-to)3037-3050
Number of pages14
JournalJournal of Medicinal Chemistry
Volume54
Issue number8
DOIs
StatePublished - Apr 28 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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