Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase

A series of conformationally restricted inhibitors of human soluble epoxide hydrolase (sEH) has been developed. Inhibition potency of the described compounds ranges from 4.2 μM to 1.1 nM against recombinant sEH. N-(1-Acetylpiperidin-4-yl)-N′-(adamant-1-yl) urea (5a) was found to be a potent inhibitor (IC50 = 7.0 nM) that was also orally bioavailable in canines.