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

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Drug Discovery

Background:

• Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor crucial for lipid metabolism, glucose homeostasis, and inflammation.
• PPARα dysfunction is linked to metabolic diseases like hypertriglyceridemia and non-alcoholic fatty liver disease, making it a key therapeutic target.

Purpose of the Study:

• To identify and optimize novel PPARα agonists for potential therapeutic applications.
• To establish a structure-activity relationship (SAR) framework for PPARα agonists.

Main Methods:

• Virtual screening of the ChemDiv database to identify lead compounds.
• Structure-activity relationship (SAR) analysis and structural modification of lead compounds.
• Synthesis of novel PPARα agonist derivatives using photocatalytic methods.
• Biological validation using luciferase reporter gene assays and HMGCS2 expression analysis.
• Molecular docking studies to elucidate binding modes.

Main Results:

• A novel PPARα agonist lead compound, LY-23, was identified.
• Fifteen novel derivatives were synthesized, with GJX-230 exhibiting the highest agonist activity (EC₅₀ = 10.42 μM).
• GJX-230 selectively upregulated HMGCS2 expression.
• Molecular docking provided insights into ligand-receptor interactions.

Conclusions:

• The study provides a series of novel chemical entities with PPARα agonist activity.
• A clear SAR framework for PPARα agonists was established.
• These findings facilitate the future development of more selective and safer PPARα agonists for metabolic diseases.