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

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§ Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy
Graduate School in Chemistry, University of Trieste, 34127 Trieste, Italy
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, 33081 Aviano, Pordenone, Italy
Department of Molecular Science and Nanosystems, Ca’ Foscari Università di Venezia, 30172 Venezia-Mestre, Italy
Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Firenze, 50139 Firenze, Italy
# Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, United States
*E-mail: [email protected]. Phone: +39-050-2219595. Fax: +39-050-2210680.
Cite this: J. Med. Chem. 2018, 61, 3, 1340–1354
Publication Date (Web):January 8, 2018
Copyright © 2018 American Chemical Society

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    Abstract Image

    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b01845.

    • General binding hypothesis for the design of diphenylpyrazole MAGL inhibitors, LC-MS/MS quantification of endocannabinoids and other metabolites, and HPLC chromatograms of the final compounds (PDF)

    • Molecular formula strings (CSV)

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