Design, synthesis, and biological evaluation of a novel dual peroxisome proliferator-activated receptor alpha/delta agonist for the treatment of diabetic kidney disease through anti-inflammatory mechanisms

• Published in: European journal of medicinal chemistry 2021-06, Vol.218, p.113388-113388, Article 113388
• Main Authors: Liu, Kai, Zhao, Xing, Qi, Xue, Hou, Dong-Liang, Li, Hao-Bin, Gu, Yu-Hao, Xu, Qing-Long
• Format: Article
• Language: English
• Subjects: Diabetic kidney disease; GFT505; Inflammation; PPAR; Sulfuretin
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113388

Diabetic kidney disease (DKD) is a major feature of the final stage of nearly all cause types of diabetes mellitus (DM). To date, few safe and effective drugs are available to treat. Peroxisome proliferator-activated receptors (PPARs), comprised of three members: PPAR-α, PPAR-δ and PPAR-γ, play a protective role in the DKD through glycemic control and lipid metabolism, whereas systemic activation of PPAR-γ causes serious side-effects in clinical trials. GFT505 is a dual PPAR-α/δ agonist, and the selectivity against PPAR-γ is still to be improved. Sulfuretin has been shown to suppress the expression of PPAR-γ and improve the pathogenesis of diabetic complications. In this study, by hybridizing the carboxylic acid of GFT505 and the parent nucleus of sulfuretin, we pioneeringly designed and synthetized a series of novel dual PPAR-α/δ agonists, expecting to provide a better benefit/risk ratio for PPARs. Of all the synthesized compounds, compound 12 was identified with highly activity on PPAR-α/δ and higher selectivity against PPAR-γ than that of GFT505 (EC50: hPPAR-α: 0.26 μM vs.0.76 μM; hPPAR-δ: 0.50 μM vs.0.73 μM; hPPAR-γ: 4.22 μM vs.2.79 μM). The molecular docking studies also depicted good binding affinity of compound 12 for PPAR-α and PPAR-δ compared to GFT505. Furthermore, compound 12 exhibited an evidently renoprotective effect on the DKD through inhibiting inflammatory process, which might at least partly via JNK/NF-κB pathways in vivo and in vitro. Overall, compound 12 hold therapeutic promise for DKD. [Display omitted] •Compound 12 shows more potent than PPAR-α/δ agonistic activity with higher selectivity against PPAR-γ compared to GFT505.•Compound 12 exerts evidently renoprotective effects through inhibiting inflammatory process in vivo and in vitro.•Compound 12 successfully takes the essence and discards the dregs from PPARs.•The design idea in this study might help us to explore better PPAR-α/δ agonists.