Discovery of Tetrazolone derivatives as potent PPARα/δ dual agonists for metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe progressive liver disease with limited therapeutic options. Dual agonists of Peroxisome Proliferator-activated Receptor α/δ (PPARα/δ) have emerged as a promising therapeutic strategy. This study describes the design, synthesis, and comprehensive drug-likeness assessment of a novel series of tetrazolone derivatives as potent and selective PPARα/δ dual agonists. A representative compound, A32, exhibited potent PPARα/δ agonistic activity (PPARα EC₅₀ = 0.36 nM; PPARδ EC₅₀ = 1.31 nM), high selectivity over PPARγ (PPARγ EC₅₀ = 160.84 nM; γ/α = 447; γ/δ = 123), and favorable druggability properties. Furthermore, A32 upregulated the expression of PPARα/δ downstream genes involved in fatty acid oxidation, including PDK4, CPT1A, and ACADVL, in HepG2 cells. Taken together, these findings identify A32 as a promising candidate for further development for the treatment of MASH.