Design,Synthesis,and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl-and 2-Benzothiazoly1-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

摘要

Fatty acid amide hydrolase(FAAH)is an intracellular serine hydrolase,which catalyzes the hydrolysis of the endocannabinoid 2V-arachidonoylethanolamide to arachidonic acid and ethanolamine.FAAH also hydrolyzes another endocannabinoid,2-arachidonoylglycerol(2-AG).However,2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase(MAGL)or a MAGL-like enzyme.Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain,inflammation,and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2.In the present study,a total of 34 novel compounds were designed,synthesized,characterized,and tested against FAAH and MAGL-like enzyme activity.Altogether,16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations(IC_(50))between 28 and 380 nM.All the active compounds belong to the structural family of carbamates.Compounds 14 and 18 were found to be the most potent FAAH inhibitors,which may serve as lead structures for novel FAAH inhibitors.