Journal of Medicinal Chemistry p. 1932 - 1958 (2019)
Update date:2022-08-15
Topics:
Granchi, Carlotta
Lapillo, Margherita
Glasmacher, Sandra
Bononi, Giulia
Licari, Cristina
Poli, Giulio
El Boustani, Maguie
Caligiuri, Isabella
Rizzolio, Flavio
Gertsch, Jürg
Macchia, Marco
Minutolo, Filippo
Tuccinardi, Tiziano
Chicca, Andrea
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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