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

• 来源期刊: 中国药理学报（英文版）
• 关键词: non-alcoholic fatty liver disease AMP-activated protein kinase AMPK activator homogeneous time-resolved fluorescence metabolic disorders ob/ob mice
• 年，卷（期）: 2018,（10）
• 页码范围: 1622-1632
• 页数: 11页
• 语种: 英文
• DOI: 10.1038/aps.2017.186

摘要

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.