Discovery of novel diarylamides as orally active diuretics targeting urea transporters

• Type of Material: Article
• Authors: Shun Zhang, Peking University; Yan Zhao, Peking University; Shuyuan Wang, Peking University; Min Li, Peking University; Yue Xu, Peking University; Jianhua Ran, Chongqing Medical University; Xiaoqiang Geng, Peking University; Jinzhao He, Peking University; Jia Meng, Peking University; Guangying Shao, Peking University; Hong Zhou, Peking University; Zemei Ge, Peking University; Guangping Chen, Emory University; Runtao Li, Peking University; Baoxue Yang, Peking University
• Language: English
• Date: 2021-01-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.apsb.2020.06.001
• Title of Journal or Parent Work: Acta Pharmaceutica Sinica B.
• Volume: 11
• Issue: 1
• Start Page: 181
• End Page: 202
• Grant/Funding Information: 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).
• Keywords: Structure optimization; Urea transporter inhibitor; Diuretic; UT-B; Oral administration; Analogs; Mice lacking; Science & Technology; Life Sciences & Biomedicine; Inhibitors; Pharmacology & Pharmacy; Drugs; Nanomolar potency
• Research Categories: Engineering, Biomedical; Biology, Physiology; Biology, Molecular; Health Sciences, Pharmacology

Abstract

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.