2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Arylimidazole Derivatives as Potent PPARδ Agonists for the Treatment of Renal Fibrosis

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

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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