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.

中文翻译：

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发现口服 AMP 激活蛋白激酶激活剂治疗高脂血症


激活 AMP 激活蛋白激酶 (AMPK) 被认为可以缓解高脂血症。以虫草素和N6-(2-羟乙基)腺苷(HEA)为先导化合物，设计、合成了一系列腺苷衍生物，并评估了其对AMPK的激活作用。最后，化合物V1被鉴定为有效的AMPK激活剂，具有降脂作用。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显着降低C57BL/6小鼠、金仓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1期临床试验。治疗 5 小时和 12 小时后，单剂量 V1（2000 毫克）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下调参与细胞凋亡过程、脂质代谢、内质网应激和肝脏炎症反应调节的基因表达。