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

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.