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

• Published in: Acta pharmacologica Sinica 2018-10, Vol.39 (10), p.1622-1632
• Main Authors: Zhang, Mei, Xie, Zhi-fu, Zhang, Run-tao, Chen, Da-kai, Gu, Min, Cui, Shi-chao, Zhang, Yang-ming, Zhang, Xin-wen, Yu, Yan-yan, Li, Jia, Nan, Fa-jun, Li, Jing-ya
• Format: Article
• Language: English
• Subjects: Accumulation; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - metabolism; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Dogs; Dyslipidemia; Enzyme Activators - chemistry; Enzyme Activators - metabolism; Enzyme Activators - therapeutic use; Fatty liver; Fluorescence; Glucose; Haplorhini; Hep G2 Cells; Humans; Immunology; Insulin; Internal Medicine; Kinases; Lipid metabolism; Lipids; Lipogenesis - drug effects; Liver; Liver - metabolism; Liver diseases; Medical Microbiology; Metabolic disorders; Metabolism; Mice; Microsomes, Liver - metabolism; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Pharmacology/Toxicology; Phosphates; Protein Domains - drug effects; Pyrazolones - chemistry; Pyrazolones - metabolism; Pyrazolones - therapeutic use; Rats; Steatosis; Structure-Activity Relationship; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.186

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.