Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

Carlotta Granchi, Giulia Bononi, Rebecca Ferrisi, Eleonora Gori, Giulia Mantini, Sandra Glasmacher, Giulio Poli, Stefano Palazzolo, Isabella Caligiuri, Flavio Rizzolio, Vincenzo Canzonieri, Tiziana Perin, J. rg Gertsch, Andrea Sodi, Elisa Giovannetti, Marco Macchia, Filippo Minutolo, Tiziano Tuccinardi, Andrea Chicca

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An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of cancer cell lines highlighted their potential as potential anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in cancer organoids derived from high grade serous ovarian cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors.
Original languageEnglish
Article number112857
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 1 Jan 2021


  • Benzoylpiperidine derivatives
  • MAGL
  • Monoacylglycerol lipase inhibitors

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