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  3. Design, synthesis and anti-diabetic evaluation of novel PPAR agonists based on functional group-oriented strategy

Design, synthesis and anti-diabetic evaluation of novel PPAR agonists based on functional group-oriented strategy

  • Eur J Med Chem. 2025 Oct 9:301:118226. doi: 10.1016/j.ejmech.2025.118226.
Sule Bai 1,  Yi Zou 1,  Yanping Li 1,  Wenjun Yang 1,  Futao Liu 1,  Jiawen Wang 1,  Zhenzhen Qie 1,  Zhen Liu 1,  Peng Yu 1,  Cen Xiang 2,  Yuou Teng 3
Affiliations

Affiliations

  • 1 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin, 300457, China.
  • 2 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin, 300457, China. Electronic address: xiangcen@tust.edu.cn.
  • 3 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin, 300457, China. Electronic address: tyo201485@tust.edu.cn.
PMID: 41075607 DOI: 10.1016/j.ejmech.2025.118226
Abstract

Peroxisome Proliferator-activated Receptor γ (PPARγ) full agonists are limited in clinical applications due to adverse effects-including adipogenesis and fluid retention-resulting from excessive activation. Using a functional group-oriented strategy, this study integrated structural features of GFT505-3d and ZLY06 to develop two novel compounds: the pan-PPAR agonist 1d and the PPARγ Agonist 2d. Both compounds significantly enhanced glucose uptake in adipocytes while exhibiting minimal adipogenic activity. In HFD/STZ-induced type 2 diabetes mellitus (T2DM) models, 1d and 2d improved Insulin resistance and hepatic lipid metabolism by suppressing PPARγ Ser273 phosphorylation in white adipose tissue and upregulating insulin-sensitizing genes such as Adiponectin, without causing weight gain or fluid retention typically associated with conventional PPARγ agonists. Transcriptome analysis further confirmed their selective modulation of PPAR signaling pathways without activation of adipogenic gene programs. These findings highlight the unique dual regulatory advantages of 1d and 2d as next-generation PPAR modulators in glucose and lipid metabolism, offering novel insights for the design of PPAR-targeted anti-diabetic drugs.

Keywords

Insulin resistance; Lipid metabolism; PPAR modulators; Ser273 phosphorylation; T2DM.

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