Yu Quanwei, Song Chao, Bi Liyun, Zhao Shuang, Lei Qian, Yang Na, Chen Hai, Wang Yuxi, He Yang, Deng Hui
Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Bioorg Med Chem. 2024 Sep 1;111:117844. doi: 10.1016/j.bmc.2024.117844. Epub 2024 Jul 23.
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.
单酰甘油脂肪酶（MAGL）是负责内源性大麻素2-花生四烯酸甘油酯（2-AG）代谢的关键酶，因其参与多种生理和病理过程，如癌症进展，而备受关注。过去，已有多种针对MAGL的共价不可逆抑制剂被报道，然而，实验证据凸显了使用这些不可逆药物的一些缺点。因此，近年来研究主要集中在开发可逆的MAGL抑制剂。在此，我们设计并合成了一系列萘酰胺衍生物（12 - 39）作为另一类可逆的MAGL抑制剂，以±34为例，其对MAGL表现出良好的抑制作用，pIC为7.1，竞争性活性蛋白质谱（ABPP）进一步证明了其对内源性MAGL的效力和选择性。此外，该化合物对包括H460、HT29、CT - 26、Huh7和HCCLM - 3在内的多种癌细胞显示出可观的抗增殖活性。这些研究最终发现了萘酰胺衍生物±34，它可能代表了一种用于开发MAGL抑制剂，特别是可逆性抑制剂的新骨架。
