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A thienopyridine, CB-20, exerts diuretic activity by inhibiting urea transporters

Authors: Min Li1, Yan Zhao2,3, Shun Zhang1, Yue Xu1, Shu-yuan Wang1, Bo-wen Li2, Jian-hua Ran4, Run-tao Li2, Bao-xue Yang1
1 State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
2 State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical Sciences, Peking University, Beijing 100191, China
3 College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China
4 Chongqing Medical University, Chongqing 400016, China
Correspondence to: Run-tao Li: lirt_1@163.com, Bao-xue Yang: baoxue@bjmu.edu.cn,
DOI: 10.1038/s41401-019-0245-5
Received: 14 February 2019
Accepted: 28 April 2019
Advance online: 18 June 2019

Abstract

Urea transporters (UTs) are transmembrane proteins selectively permeable to urea and play an important role in urine concentration. UT-knockout mice exhibit the urea-selective urine-concentrating defect, without affecting electrolyte balance, suggesting that UT-B inhibitors have the potential to be developed as novel diuretics. In this study, we characterized a novel compound 5-ethyl-2-methyl-3-amino-6-methylthieno[2,3-b]pyridine-2,5-dicarboxylate (CB-20) with UT inhibitory activity as novel diuretics with excellent pharmacological properties. This compound was discovered based on high-throughput virtual screening combined with the erythrocyte osmotic lysis assay. Selectivity of UT inhibitors was assayed using transwell chambers. Diuretic activity of the compound was examined in rats and mice using metabolic cages. Pharmacokinetic parameters were detected in rats using LC–MS/MS. Molecular docking was employed to predict the potential binding modes for the CB-20 with human UT-B. This compound dose-dependently inhibited UT-facilitated urea transport with IC50 values at low micromolar levels. It exhibited nearly equal inhibitory activity on both UT-A1 and UT-B. After subcutaneous administration of CB-20, the animals showed polyuria, without electrolyte imbalance and abnormal metabolism. CB-20 possessed a good absorption and rapid clearance in rat plasma. Administration of CB-20 for 5 days did not cause significant morphological abnormality in kidney or liver tissues of rats. Molecular docking showed that CB-20 was positioned near several residues in human UT-B, including Leu364, Val367, and so on. This study provides proof of evidence for the prominent diuretic activity of CB-20 by specifically inhibiting UTs. CB-20 or thienopyridine analogs may be developed as novel diuretics.
Keywords: diuretics; thienopyridine; urea transporter; electrolytes; drug discovery

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