Design, Synthesis, and Biological Evaluation of Arylimidazole Derivatives as Potent PPARδ Agonists for the Treatment of Renal Fibrosis

  • J Med Chem. 2026 Feb 26;69(4):4469-4492. doi: 10.1021/acs.jmedchem.5c03132.
Zhiqi Feng  1  2 ,  Junkai Xie  1 ,  Dongliang Hou  1 ,  Zhuoxin Fu  1 ,  Suyang Sun  1 ,  Xinpeng Liu  1 ,  Gang Sun  1 ,  Runan Zheng  3 ,  Liu Liu  1 ,  Qinglong Xu  1 ,  Xiaoan Wen  1 ,  Daoxu Zhang  4 ,  Haoliang Yuan  1 ,  Hongbin Sun  1  2 ,  Liang Dai  1  2
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
  • 3. Animal Experiment Center of China Pharmaceutical University, China Pharmaceutical University, Nanjing 211198, China.
  • 4. Harbin Medisan Pharmaceutical Co., Ltd., Harbin 150000, China.
PMID: 41667192 DOI: 10.1021/acs.jmedchem.5c03132
Abstract

Peroxisome proliferator-activator receptor δ (PPARδ) is ubiquitously expressed in the kidney, and its agonists are increasingly being recognized as a potential therapeutic strategy for renal diseases. In this work, we developed a series of arylimidazole derivatives as potent PPARδ agonists. Among them, compound 16a exhibited potent PPARδ agonistic activity (EC50 = 0.50 nM) and high selectivity over PPARα/γ and some Other nuclear receptors. The X-ray cocrystal structure revealed the binding mode of 16a and PPARδ at 1.94 Å resolution. Remarkably, compound 16a exhibited acceptable pharmacokinetic properties and good safety profiles in vivo and showed antirenal fibrosis effects in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Mechanistically, 16a activated PPARδ to restore fatty acid oxidation to attenuate TGF-β1-induced renal fibroblast activation. Collectively, 16a warrants further investigation as a promising drug candidate for treating renal fibrosis.

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