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J Med Chem. 2019 Feb 28;62(4):1932-1958. doi: 10.1021/acs.jmedchem.8b01483. Epub 2019 Feb 11.

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

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Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
Institute of Biochemistry and Molecular Medicine, NCCR TransCure , University of Bern , CH-3012 Bern , Switzerland.
Pathology Unit, Department of Molecular Biology and Translational Research , National Cancer Institute and Center for Molecular Biomedicine , 33081 Aviano , Pordenone , Italy.
Doctoral School in Molecular Biomedicine , University of Trieste , 34100 Trieste , Italy.
Department of Molecular Sciences and Nanosystems , Ca' Foscari University , 30123 Venezia , Italy.


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.

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