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Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors. 2018
Mojgan Aghazadeh Tabrizi, and
Pier Giovanni Baraldi, and
Stefania Baraldi, and
Emanuela Ruggiero, and
Lucia De Stefano, and
Flavio Rizzolio, and
Lorenzo Di Cesare Mannelli, and
Carla Ghelardini, and
Andrea Chicca, and
Margherita Lapillo, and
Jürg Gertsch, and
Clementina Manera, and
Marco Macchia, and
Adriano Martinelli, and
Carlotta Granchi, and
Filippo Minutolo, and
Tiziano Tuccinardi
Department of Chemical and Pharmaceutical Sciences, University of Ferrara , 44121 Ferrara, Italy.
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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