State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street 1, Xicheng District, Beijing 100050, China.
J Med Chem. 2024 May 23;67(10):7870-7890. doi: 10.1021/acs.jmedchem.3c01267. Epub 2024 May 13.
Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.
激活 AMP 激活的蛋白激酶 (AMPK) 被认为可以减轻高血脂症。以虫草素和 N6-(2-羟乙基)腺苷 (HEA) 为先导化合物，设计、合成了一系列基于腺苷的衍生物，并对其激活 AMPK 的活性进行了评价。最终，化合物 V1 被鉴定为一种具有降脂作用的强效 AMPK 激活剂。分子对接和圆二色性表明，V1 通过与 AMPK 的γ亚基结合发挥其活性。V1 显著降低了 C57BL/6 小鼠、金黄地鼠和恒河猴的血清低密度脂蛋白胆固醇水平。V1 被选为临床化合物，并完成了 1 期临床试验。单次给予 2000 mg 的 V1 后，在 5 和 12 小时时可增加人红细胞中的 AMPK 激活。RNA 测序数据表明，V1 通过激活 AMPK，下调了肝脏中与凋亡过程、脂质代谢、内质网应激和炎症反应调节相关的基因的表达。
