Jin Jiyu, Huang Suling, Wang Lei, Leng Ying, Lu Wei
School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Chem Biol Drug Des. 2017 Dec;90(6):1122-1133. doi: 10.1111/cbdd.13029. Epub 2017 Jun 26.
Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme that mobilizes fatty acids from cellular triglyceride stores. Metabolic syndrome, which refers to a group of abnormalities that occur together and increase the risk of coronary artery disease, stroke, type 2 diabetes, and cachexia, can be treated using ATGL-specific inhibitors. Atglistatin (1) is the first small-molecule inhibitor of ATGL. In this study, we designed and synthesized 29 Atglistatin derivatives and evaluated their inhibition of forskolin-stimulated lipolysis in 3T3-L1 adipocytes as an indicator of their potential to inhibit ATGL in adipose tissues. Among all the tested Atglistatin analogs, we previously found that the thiourea compound 9e showed potent ATGL inhibitory activity in vitro, which was much stronger than that of Atglistatin, and its inhibitory activity in vivo was similar to that of Atglistatin. This tool compound could be used to study the pathophysiology and druggability of ATGL in animal models of metabolic disease and cachexia.
脂肪甘油三酯脂肪酶（ATGL）是一种限速酶，可从细胞内甘油三酯储存中动员脂肪酸。代谢综合征是指一组共同出现且会增加冠状动脉疾病、中风、2型糖尿病和恶病质风险的异常情况，可使用ATGL特异性抑制剂进行治疗。阿特格列汀（1）是首个ATGL小分子抑制剂。在本研究中，我们设计并合成了29种阿特格列汀衍生物，并评估了它们对福斯可林刺激的3T3-L1脂肪细胞脂解的抑制作用，以此作为它们抑制脂肪组织中ATGL潜力的指标。在所有测试的阿特格列汀类似物中，我们之前发现硫脲化合物9e在体外表现出强效的ATGL抑制活性，比阿特格列汀强得多，且其体内抑制活性与阿特格列汀相似。这种工具化合物可用于研究代谢疾病和恶病质动物模型中ATGL的病理生理学和药物可及性。
