Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.
A series of 1,3-disubstituted and 1,3,3-trisubstituted isoxazolyl- and adamantyl-functionalized ureas was synthesized. The resulting compounds are potent inhibitors of soluble epoxide hydrolase. The compounds were obtained in high yields under mild conditions. Water solubility of the synthesized ureas was found to exceed significantly that of known analogs
