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

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-(cyclopropimecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyllurea (52) showed a 7-fold increase in potency, a 65-fold increase in C-max and a 3300-fold increase in A UC over its adamant:me 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.