| abstract |
(57) [Summary]nAn oleamide hydrolase inhibitor involved in the hydrolysis of endogenous sleep-inducing lipid (1, cis-9-octadeceneamide) was designed and synthesized. The most potent inhibitors have an electrophilic carbonyl group capable of reversibly forming a (thio) hemiacetal or (thio) hemiketal that mimics the transition state of serine or cysteine protease catalysis. In particular, the tightly bound α-ketoethyl ester inhibitor 8 (1.4 nM) and the trifluoromethyl ketone inhibitor 12 (1.2 nM) were found to have exceptional inhibitory activity. In addition to the inhibitory activity, some of the inhibitors showed agonistic activity to induce sleep induction in experimental animals. |