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.
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| http://dx.doi.org/10.1021/jm100691c | DOI Listing |
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