2. Academic Validation
  3. Discovery of Tetrazolone derivatives as potent PPARα/δ dual agonists for metabolic dysfunction-associated steatohepatitis

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

  • Bioorg Chem. 2026 Jul 5:175:109764. doi: 10.1016/j.bioorg.2026.109764.
Yaning Yao 1,  Jiahui Feng 1,  Hao Yue 1,  Jie Wu 1,  Minghui Tong 2,  Xuan Shi 2,  Zhenyu Miao 2,  Han Wang 2,  Mingze Qin 3,  Ping Gong 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2 3D BioOptima, 1338 Wuzhong Avenue, Suzhou 215104, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 41880786 DOI: 10.1016/j.bioorg.2026.109764
Abstract

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.

Keywords

MASH; Selective PPARα/δ dual agonists; Tetrazolone derivatives.

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