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

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

Published In J Med Chem, (2011 Apr 28)

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.

PubMed ID: 21434686 Exiting the NIEHS site

MeSH Terms: Animals; Cyclooxygenase 2/drug effects*; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry*; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Models, Molecular; Pyrazoles/chemical synthesis; Pyrazoles/chemistry*; Pyrazoles/pharmacology*; Rats; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Urea/chemistry*

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