Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives.
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| Abstract |
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.
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| Authors | Giulia Bononi, Miriana Di Stefano, Giulio Poli, Gabriella Ortore, Philip Meier, Francesca Masetto, Isabella Caligiuri, Flavio Rizzolio, Marco Macchia, Andrea Chicca, Amir Avan, Elisa Giovannetti, Chiara Vagaggini, Annalaura Brai, Elena Dreassi, Massimo Valoti, Filippo Minutolo, Carlotta Granchi, Jürg Gertsch, Tiziano Tuccinardi |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 10 Pg. 7118-7140 (05 26 2022) ISSN: 1520-4804 [Electronic] United States |
| PMID | 35522977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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