Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
Institute of Biochemistry and Molecular Medicine, NCCR TransCure , University of Bern , CH-3012 Bern , Switzerland.
J Med Chem. 2019 Feb 28;62(4):1932-1958. doi: 10.1021/acs.jmedchem.8b01483. Epub 2019 Feb 11.
Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
单酰基甘油脂肪酶（MAGL）是降解内源性大麻素 2-花生四烯酸甘油的酶，它参与了许多生理和病理过程。MAGL 的治疗潜力与包括癌症在内的几种疾病有关。MAGL 抑制剂的发展受到与 MAGL 失活延长相关的副作用的极大限制。重要的是，在体内使用可逆的 MAGL 抑制剂可能更为可取，但目前仅开发了少数几种可逆化合物。在本研究中，对先前开发的一类 MAGL 抑制剂进行了结构优化，鉴定出化合物 23，它被证明是一种非常有效的可逆 MAGL 抑制剂（IC = 80 nM），对 MAGL 具有选择性，对其他主要内源性大麻素系统成分无活性，对一系列癌细胞系具有有前途的抗增殖活性，并能够在细胞基础和体内测定中阻断 MAGL。
