title: Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase.
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.
authors: Department of Entomology, University of California, Davis, California 95616-8584, United States.
authors: Sung Hee
authors: SH
authors: Hwang
authors: Karen M
authors: KM
authors: Wagner
authors: Christophe
authors: C
authors: Morisseau
authors: Jun-Yan
authors: JY
authors: Liu
authors: Hua
authors: H
authors: Dong
authors: Aaron T
authors: AT
authors: Wecksler
authors: Bruce D
authors: BD
authors: Hammock
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D014508:Urea; D051546:Cyclooxygenase 2; D004851:Epoxide Hydrolases