Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome

  • Eur J Med Chem. 2021 Dec 5;225:113807. doi: 10.1016/j.ejmech.2021.113807.
Zheng Li  1 ,  Qiang Ren  2 ,  Zongtao Zhou  3 ,  Zongyu Cai  3 ,  Bin Wang  3 ,  Jing Han  4 ,  Luyong Zhang  5
Affiliations
  • 1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: [email protected].
  • 2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 3. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 4. School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, 221116, PR China.
  • 5. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 34455359 DOI: 10.1016/j.ejmech.2021.113807
Abstract

The peroxisome proliferator-activated receptors (PPARs) exert vital function in the regulation of energy metabolism, which were considered as promising targets of metabolic syndrome. Until now, PPARδ/γ dual agonist is rarely reported, and thereby the pharmacologic action of PPARδ/γ dual agonist is still unclear. In this study, we identified a dual PPARδ/γ partial agonist 6 (ZLY06) based on the cyclization strategy of PPARα/δ dual agonist GFT505. ZLY06 revealed excellent pharmacokinetic profiles suitable for oral medication. Moreover, ZLY06 markedly improved glucolipid metabolism without weight gain, and alleviated fatty liver by promoting the β-oxidation of fatty acid and inhibiting hepatic lipogenesis. In contrast, weight gain and hepatic steatosis were observed in Rosiglitazone, a widely used PPARγ full agonist. All of these results indicated that ZLY06 exhibits potential benefits on metabolic syndrome, while no adverse effects related to PPARγ full agonist.

Keywords
Diabetes; Fatty liver; Insulin resistance; Metabolic syndrome; PPAR.
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