Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor

Monoacylglycerol
lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol,
and it is involved in several physiological and pathological processes.
The therapeutic potential of MAGL is linked to several diseases, including
cancer. The development of MAGL inhibitors has been greatly limited
by the side effects associated with the prolonged MAGL inactivation.
Importantly, it could be preferable to use reversible MAGL inhibitors
in vivo, but nowadays only few reversible compounds have been developed.
In the present study, structural optimization of a previously developed
class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor
(IC50 = 80 nM), selective for MAGL over the other main
components of the endocannabinoid system, endowed of a promising antiproliferative
activity in a series of cancer cell lines and able to block MAGL both
in cell-based as well as in vivo assays.