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

Carlotta Granchi, Margherita Lapillo, Sandra Glasmacher, Giulia Bononi, Cristina Licari, Giulio Poli, Maguie El Boustani, Isabella Caligiuri, Flavio Rizzolio, Jürg Gertsch, Marco Macchia, Filippo Minutolo, Tiziano Tuccinardi, Andrea Chicca

Research output: Contribution to journalArticlepeer-review

Abstract

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 (IC 50 = 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.

Original languageEnglish
Pages (from-to)1932-1958
Number of pages27
JournalJournal of Medicinal Chemistry
Volume62
Issue number4
DOIs
Publication statusPublished - Feb 28 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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