Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase.
Article Details
- CitationCopy to clipboard
Hwang SH, Wagner KM, Morisseau C, Liu JY, Dong H, Wecksler AT, Hammock BD
Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase.
J Med Chem. 2011 Apr 28;54(8):3037-50. doi: 10.1021/jm2001376. Epub 2011 Apr 5.
- PubMed ID
- 21434686 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Celecoxib Prostaglandin G/H synthase 2 IC 50 (nM) 10 N/A N/A Details Indomethacin Prostaglandin G/H synthase 2 IC 50 (nM) 17000 N/A N/A Details Rofecoxib Prostaglandin G/H synthase 2 IC 50 (nM) 2000 N/A N/A Details