PPARδ agonist 13

PPARδ agonist13 is a potent, selective, and orally active PPARδ agonist with an EC50 value of 0.50 nM. It binds to the ligand binding pocket of PPARδ, enhancing the expression of PPARδ target genes. This compound inhibits kidney fibroblast activation, restores fatty acid oxidation, and reduces TGF-β1-induced kidney fibroblast activation. In a unilateral ureteral obstruction mouse model, it demonstrates anti-renal fibrosis effects. PPARδ agonist13 is applicable in research related to renal fibrosis.

PPARδ:0.5 nM (EC50)

PPARδ agonist 13 (Compound 16a) demonstrates dose-dependent upregulation of PPARδ target genes in HK2 cells at concentrations of 10-1000 nM over 6 hours. In Cos-7 cells, it exhibits high selectivity for PPARδ with negligible PPARγ agonistic activity observed only at the highest concentration tested, 5 μM, over 16 hours at 0.2-5 μM. When interacting directly with purified PPARδ LBD protein, at 1-30 μM over 3 minutes, the compound demonstrates an ability to do so by reducing ANS fluorescence. Additionally, PPARδ agonist 13 does not inhibit hERG potassium channels in hERG knock-in HEK293 cells at 0.3-30 μM, suggesting a lower cardiovascular risk. Lastly, at concentrations of 2.5-10 nM for 23 hours, it dose-dependently attenuates TGF-β1-induced activation of NRK-49F renal fibroblasts, reducing the expression of α-SMA and fibronectin at 2.5 and 10 nM.

PPARδ agonist 13, when administered at doses of 3-10 mg/kg via gavage daily for 13 days, mitigates kidney fibrosis induced by unilateral ureteral obstruction in male C57BL/6JNifdc mice in a dose-dependent manner by downregulating fibrosis gene expression, reducing inflammation, inhibiting apoptosis, and restoring fatty acid oxidation pathways. Additionally, PPARδ agonist 13 shows low toxicity in C57BL/6JNifdc mice when given continuously at 100 mg/kg for 14 days, or as a single dose of 2000 mg/kg, also administered via gavage.