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

Mei ZHANG1, Zhi-fu XIE1,2, Run-tao ZHANG1, Da-kai CHEN1, Min GU1, Shi-chao CUI1, Yang-ming ZHANG1, Xin-wen ZHANG1, Yan-yan YU1, Jia LI1, Fa-jun NAN1, Jing-ya LI1
1 State Key Laboratory of Drug Research, the National Drug Screening Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Fa-jun NAN:, Jing-ya LI:,
DOI: 10.1038/aps.2017.186
Received: 9 October 2017
Accepted: 21 December 2017
Advance online: 24 May 2018


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.
Keywords: non-alcoholic fatty liver disease; AMP-activated protein kinase; AMPK activator; homogeneous time-resolved fluorescence; metabolic disorders; ob/ob mice

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