Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents.

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common hepatic disease, while no drug was approved until now. The previous study reported that the quadruple FFA1/PPAR-α/γ/δ agonist RLA8 provided better efficacy than obeticholic acid on NASH. In the present study, two design strategies were introduced to explore better quadruple FFA1/PPAR-α/γ/δ agonists with improved metabolic stability. These efforts ultimately resulted in the identification of ZLY18, a quadruple FFA1/PPAR-α/γ/δ agonist with twice higher metabolic half-life than RLA8 in the liver microsome. In the triton-1339W-induced hyperlipidemic model, ZLY18 reversed hyperlipidemia to an almost normal level, which exhibited far stronger lipid-lowering effects than that of RLA8. Moreover, ZLY18 significantly decreased steatosis, hepatocellular ballooning, inflammation and liver fibrosis in NASH model even better than RLA8. Further mechanism studies suggested that ZLY18 exerts stronger effects than RLA8 on the regulation of the gene related to lipid synthesis, oxidative stress, inflammation and fibrosis. In addition, ZLY18 is more effective than pirfenidone in the prevention of CCl4-induced liver fibrosis. Besides, ZLY18 has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg. Therefore, ZLY18 represents a novel and highly promising quadruple FFA1/PPAR-α/γ/δ agonist worth of further investigation and development.

• Authors: Zongtao Zhou, Qiang Ren, Shixuan Jiao, Zongyu Cai, Xinqian Geng, Liming Deng, Bin Wang, Lijun Hu, Luyong Zhang, Ying Yang, Zheng Li
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 229 Pg. 114061 (Feb 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 34954593 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Chenodeoxycholic Acid
• Hypoglycemic Agents
• obeticholic acid
• Peroxisome Proliferator-Activated Receptors
• Receptors, G-Protein-Coupled
• RLA8

Topics

• Animals
• Humans
• Male
• Chenodeoxycholic Acid (analogs & derivatives, chemistry)
• Drug Discovery
• Gene Expression Regulation (drug effects)
• Hypoglycemic Agents (chemistry, pharmacokinetics)
• Liver Cirrhosis (prevention & control)
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Models, Molecular
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Oxidative Stress (drug effects)
• Peroxisome Proliferator-Activated Receptors (agonists)
• Protein Binding
• Receptors, G-Protein-Coupled (agonists)
• Structure-Activity Relationship
• Mice