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

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

来源：Journal of Medicinal Chemistry, 2018, 61(3): 1340-1354.

DOI：10.1021/acs.jmedchem.7b01845

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 mu M, K-i = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), alpha/beta-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.

• 出版日期2018-2-8