A new potent and selective peroxisome proliferator-activated receptor alpha partial agonist displays anti-steatotic effects In vitro and behaves as a safe hypolipidemic and hypoglycemic agent in a diabetic mouse model

A rational drug design approach led to the synthesis of three pairs of enantiomers derived from the peroxisome proliferator-activated receptor (PPAR) pan agonist AL29-26, identifying ( S )- 2 as a potent and selective PPARα partial agonist. Molecular docking and molecular dynamics simulations elucidated the binding modes of ( S )- 2 within the ligand-binding domains of PPARα and PPARγ. In vitro, ( S )- 2 demonstrated significant anti-steatotic effects, upregulating key PPARα target genes involved in lipid metabolism. In vivo, ( S )- 2 exhibited hypolipidemic and antihyperglycemic activity in a diabetic mouse model, outperforming fenofibrate in lowering blood glucose and lipid levels, while showing no toxicity in major organs (artery, kidney, liver, pancreas). The therapeutic effects of (( S )- 2 were attributed to its PPARα selectivity, reduced activation of PPARγ, and mild protein tyrosine phosphatase 1B (PTP1B) inhibition. These findings highlight ( S )- 2 as a promising lead compound for the development of safer and more effective treatments for dyslipidemic type 2 diabetes. • ( S )- 2 is a potent and selective PPARα partial agonist with anti-steatotic effects. • Molecular docking and MD simulations elucidate the stereoselective binding of ( S )- 2. • ( S )- 2 reduces lipid accumulation and upregulates key PPARα target genes in vitro. • In vivo, ( S )- 2 shows superior hypolipidemic and hypoglycemic effects vs. fenofibrate. • ( S )- 2 is well-tolerated and enhances arterial integrity without major organ toxicity.