jm7b01845_si_001.pdf (8.26 MB)
Download file

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

Download (8.26 MB)
journal contribution
posted on 08.01.2018, 00:00 by 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
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.