Design, synthesis and activity evaluation of a novel PPARα agonist based on virtual screening.

Peroxisome proliferator-activated receptor α (PPARα) represents a critical therapeutic target for dyslipidemia. To discover novel scaffold agonists, we used Pemafibrate as a template to construct a focused chemical library with the infiniSee software. An integrated virtual screening approach, including molecular docking, MM-GBSA binding free energy calculations, ADMET profiling, and visual inspection, was applied to identify a hit compound. Subsequent structural optimization led to the synthesis of 40 derivatives. Among the tested compounds, XYQ3-B11 was identified as the most potent PPARα activator. In the luciferase reporter assay, XYQ3-B11 exhibited an EC50 value of 8.33 μM, better than the reference agonist WY14643 (EC50 = 16.10 μM). Notably, XYQ3-B11 possesses a distinctive hybrid architecture, comprising a central pyridine ring, a 2-fluorobenzoate moiety, and an indole-derived side chain. These findings highlight XYQ3-B11 as a promising novel chemotype for the start of development of PPARα agonists.