Design, synthesis, and activity evaluation of novel potential PPARα agonists

Peroxisome proliferator-activated receptor α (PPARα), an important member of the nuclear receptor superfamily, plays a crucial role in regulating lipid metabolism, glucose homeostasis, and inflammation. Its dysfunction is associated with metabolic diseases such as hypertriglyceridemia and non-alcoholic fatty liver disease, making PPARα a significant therapeutic target. In this study, a potential novel PPARα agonist lead compound, LY-23 (EC₅₀ = 11.91 μM), was identified through virtual screening of the ChemDiv database followed by biological validation. Based on preliminary structure-activity relationship (SAR) analysis, structural modification and optimization of three key regions of LY-23 were carried out, resulting in fifteen structurally novel derivatives, whose synthetic routes incorporated photocatalytic steps as an advanced synthetic strategy. Among these derivatives, compound GJX-230 (EC₅₀ = 10.42 μM) exhibited the highest agonist activity in a luciferase reporter gene assay. Further studies demonstrated that GJX-230 selectively upregulated the expression of HMGCS2. Molecular docking studies elucidated the binding modes of the active compounds within the PPARα ligand-binding domain. This work not only provides a series of new chemical foundations, but also establishes a clear SAR framework and preliminary biological insights, which may facilitate the future development of more selective and safer PPARα agonists.