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  3. Benzothiazole amide analogues as antagonists of TRPC 6 channels: A therapeutic approach for kidney fibrosis

Benzothiazole amide analogues as antagonists of TRPC 6 channels: A therapeutic approach for kidney fibrosis

  • Eur J Med Chem. 2025 Jul 5:291:117628. doi: 10.1016/j.ejmech.2025.117628.
Chunlin Ren 1,  Qiding Xu 1,  Qiusi Luo 1,  Xue Qiao 1,  Taotao Ding 1,  Wumei Wang 2,  Xiaodong Zeng 3,  Cheng Chen 4,  Yuling Xiao 5,  Xuechuan Hong 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
  • 2 Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Shenzhen Institute of Wuhan University, Shenzhen, 518057, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: xdzeng@baridd.ac.cn.
  • 4 Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. Electronic address: chencheng321@whu.edu.cn.
  • 5 Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: xiaoyl@whu.edu.cn.
  • 6 Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China; Shenzhen Institute of Wuhan University, Shenzhen, 518057, China. Electronic address: xhy78@whu.edu.cn.
PMID: 40267878 DOI: 10.1016/j.ejmech.2025.117628
Abstract

Transient receptor potential canonical 6 (TRPC6) channels, which function as receptor-operated, non-selective cation channels, are widely expressed in the kidney, lungs, and brain. Within these organs, they play crucial roles in regulating diverse physiological processes and contribute to the pathogenesis of various disorders. The resolution of the cryo-electron microscopy structure of TRPC6 has significantly advanced our understanding of its molecular mechanisms, thereby providing a robust platform for structure-based drug design. Building upon compound 1S as a lead, we developed and synthesized a series of benzothiazole derivatives, ultimately identifying compound X26 as a potent TRPC6 antagonist with an IC50 of 0.97 μM. In vitro administration of X26 significantly suppressed TGF-β1-induced myofibroblast differentiation in HK-2 cells, as evidenced by a reduced expression of α-SMA, Collagen I, and fibronectin. Furthermore, in a unilateral ureteral obstruction (UUO)-induced kidney fibrosis mouse model, treatment with X26 resulted in a substantial reduction in serum urea nitrogen, serum creatinine, and urinary protein levels, as well as a decrease in renal Collagen deposition. These findings establish X26 as a promising lead for the development of TRPC6 antagonists and therapeutic interventions for kidney fibrosis.

Keywords

Antagonist; Benzothiazole derivatives; Renal fibrosis; Transient receptor potential canonical 6 channels; Unilateral ureteral obstruction.

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