Synthesis and Structure鈭扐ctivity Relationship Studies of Urea-Containing Pyrazoles as Dual Inhibitors of Cyclooxygenase-2 and Soluble Epoxide Hydrolase

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• 作者：Sung Hee Hwang ; Karen M. Wagner ; Christophe Morisseau ; Jun-Yan Liu ; Hua Dong ; Aaron T. Wecksler ; Bruce D. Hammock
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：3037-3050
• 全文大小：1155K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

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.