Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors

Mojgan Aghazadeh Tabrizi, Pier Giovanni Baraldi, Stefania Baraldi, Emanuela Ruggiero, Lucia De Stefano, Flavio Rizzolio, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Andrea Chicca, Margherita Lapillo, Jürg Gertsch, Clementina Manera, Marco Macchia, Adriano Martinelli, Carlotta Granchi, Filippo Minutolo, Tiziano Tuccinardi

Research output: Contribution to journalArticle

Abstract

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, antinociceptive, and anticancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of reversible MAGL inhibitors. Among them, compound 26 showed to be a potent MAGL inhibitor (IC50 = 0.51 μM, Ki = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), α/β-hydrolase domain-containing 6 (ABHD6), and 12 (ABHD12). Interestingly, this compound also possesses antiproliferative activities against two different cancer cell lines and relieves the neuropathic hypersensitivity induced in vivo by oxaliplatin.

Original languageEnglish
Pages (from-to)1340-1354
Number of pages15
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
DOIs
Publication statusPublished - Feb 8 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Aghazadeh Tabrizi, M., Baraldi, P. G., Baraldi, S., Ruggiero, E., De Stefano, L., Rizzolio, F., Di Cesare Mannelli, L., Ghelardini, C., Chicca, A., Lapillo, M., Gertsch, J., Manera, C., Macchia, M., Martinelli, A., Granchi, C., Minutolo, F., & Tuccinardi, T. (2018). Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors. Journal of Medicinal Chemistry, 61(3), 1340-1354. https://doi.org/10.1021/acs.jmedchem.7b01845