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.