Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice


Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic steatosis. NAFLD is closely linked to obesity, insulin resistance and dyslipidemia. AMP-activated protein kinase (AMPK) functions as an energy sensor and plays a central role in regulating lipid metabolism. In this study, we identified a series of novel pyrazolone AMPK activators using a homogeneous time-resolved fluorescence assay (HTRF) based on the AMPKα2β1γ1 complex. Compound 29 (C29) is a candidate compound that directly activated the kinase domain of AMPK with an EC50 value of 2.1–0.2 μmol/L and acted as a non-selective activator of AMPK complexes. Treatment of HepG2 cells with C29 (20, 40 μmol/L) dose-dependently inhibited triglyceride accumulation. Chronic administration of C29 (10, 30 mg/kg every day, po, for 5 weeks) significantly improved lipid metabolism in both the liver and the plasma of ob/ob mice. These results demonstrate that the AMPK activators could be part of a novel treatment approach for NAFLD and associated metabolic disorders.

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This work was supported by the National Natural Science Foundation of China (No 81502910, 81273566 and 81673489), the Shanghai Commission of Science and Technology (No 15ZR1447900 and 14431902800), the Youth Innovation Association of Chinese Academy of Sciences (Mei ZHANG), and the National Key Research and Development Program of China (No 2016YFC1305500).

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Correspondence to Fa-jun Nan or Jing-ya Li.

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  • non-alcoholic fatty liver disease
  • AMP-activated protein kinase
  • AMPK activator
  • homogeneous time-resolved fluorescence
  • metabolic disorders
  • ob/ob micer