1-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure−Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory Pain

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• 作者：Tristan E. Rose ; Christophe Morisseau ; Jun-Yan Liu ; Bora Inceoglu ; Paul D. Jones ; James R. Sanborn ; Bruce D. Hammock
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：7067-7075
• 全文大小：890K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure−activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in C_max, and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.