Department of Chemical and Pharmaceutical Sciences, University of Ferrara , 44121 Ferrara, Italy.
Graduate School in Chemistry, University of Trieste , 34127 Trieste, Italy.
J Med Chem. 2018 Feb 8;61(3):1340-1354. doi: 10.1021/acs.jmedchem.7b01845. Epub 2018 Jan 22.
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 (IC = 0.51 μM, K = 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.
单酰甘油脂肪酶（MAGL）是一种丝氨酸水解酶，在降解内源性大麻素神经递质 2-花生四烯酸甘油的过程中发挥重要作用，该神经递质与许多生理过程有关。除了将 MAGL 抑制剂用作抗炎、镇痛和抗癌药物的可能用途外，由于该酶的不可逆抑制所引起的不良作用，其应用遇到了障碍。可逆 MAGL 抑制剂的可能应用最近才被探索，主要是由于缺乏具有有效可逆抑制活性的已知化合物。在这项工作中，我们报告了一系列新的可逆 MAGL 抑制剂。其中，化合物 26 被证明是一种有效的 MAGL 抑制剂（IC = 0.51 μM，K = 412 nM），对脂肪酸酰胺水解酶（FAAH）、α/β-水解酶结构域包含 6 型（ABHD6）和 12 型（ABHD12）具有良好的选择性。有趣的是，这种化合物还对两种不同的癌细胞系具有抗增殖活性，并缓解奥沙利铂体内诱导的神经病理性过敏。
