Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives

Monoacylglycerol lipase (MAGL) is the enzymeresponsible for the metabolism of 2-arachidonoylglycerol in thebrain and the hydrolysis of peripheral monoacylglycerols. Manystudies demonstrated beneficial effects deriving from MAGLinhibition for neurodegenerative diseases, inflammatory patholo-gies, and cancer. MAGL expression is increased in invasive tumors,furnishing free fatty acids as pro-tumorigenic signals and for tumorcell growth. Here, a new class of benzylpiperidine-based MAGLinhibitors was synthesized, leading to the identification of13,which showed potent reversible and selective MAGL inhibition.Associated with MAGL overexpression and the prognostic role inpancreatic cancer, derivative13showed antiproliferative activityand apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed asynergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-basedMAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer.