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Author Notes:

Correspondence: Tel./fax: +86 10 82805954, baoxue@bjmu.edu.cn, (Runtao Li), or +86 10 82805622, lirt@bmju.edu.cn (Baoxue Yang)

Author contributions: Shun Zhang, Yan Zhao, Runtao Li, Baoxue Yang: designed experiments. Shun Zhang, Yan Zhao, Shuyuan Wang, Min Li, Yue Xu: carried out experiments. Shun Zhang, Yan Zhao, Jianhua Ran, Xiaoqiang Geng, Jinzhao He, Jia Meng, Guangying Shao, Hong Zhou, Zemei Ge, Guangping Chen: analyzed experimental results.

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Disclosures: The authors declare no competing financial interests.


Research Funding:

This work was supported by National Natural Science Foundation of China (Grant Nos.81620108029, 81974083, and 81330074), and Beijing Natural Science Foundation grant 7172113 (China).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Pharmacology & Pharmacy
  • Urea transporter inhibitor
  • Diuretic
  • Structure optimization
  • Oral administration
  • UT-B
  • Mice lacking
  • Nanomolar potency
  • Inhibitors
  • Analogs
  • Drugs

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

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Journal Title:

Acta Pharmaceutica Sinica B.


Volume 11, Number 1


, Pages 181-202

Type of Work:

Article | Final Publisher PDF


Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro UT inhibitory activity at the submicromolar level. The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 μmol/L, respectively. Further investigation suggested that 8 μmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

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© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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