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

Monoacylglycerol
lipase (MAGL) is the enzyme responsible for the
metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis
of peripheral monoacylglycerols. Many studies demonstrated beneficial
effects deriving from MAGL inhibition for neurodegenerative diseases,
inflammatory pathologies, and cancer. MAGL expression is increased
in invasive tumors, furnishing free fatty acids as pro-tumorigenic
signals and for tumor cell growth. Here, a new class of benzylpiperidine-based
MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition.
Associated with MAGL overexpression and the prognostic role in pancreatic
cancer, derivative 13 showed antiproliferative activity
and apoptosis induction, as well as the ability to reduce cell migration
in primary pancreatic cancer cultures, and displayed a synergistic
interaction with the chemotherapeutic drug gemcitabine. These results
suggest that the class of benzylpiperidine-based MAGL inhibitors have
potential as a new class of therapeutic agents and MAGL could play
a role in pancreatic cancer.