Discovery of Oral AMP-Activated Protein Kinase Activators for Treating Hyperlipidemia

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.