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Eur J Med Chem. 2019 Jun 15;172:131-142. doi: 10.1016/j.ejmech.2019.03.060. Epub 2019 Apr 1.

Discovery and optimization of thienopyridine derivatives as novel urea transporter inhibitors.

Author information

1
State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical Sciences, Peking University, 100191, PR, China; College of Pharmacy, Inner Mongolia Medical University, 010110, PR, China.
2
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, PR, China.
3
State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical Sciences, Peking University, 100191, PR, China.
4
State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical Sciences, Peking University, 100191, PR, China. Electronic address: lirt@bjmu.edu.cn.
5
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, PR, China. Electronic address: baoxue@bjmu.edu.cn.

Abstract

Urea transporters (UTs) play an important role in the urine concentrating mechanism and are recognized as novel targets for developing small molecule inhibitors with salt-sparing diuretic activity. Thienoquinoline derivatives, a class of novel UT-B inhibitors identified by our group, play a significant diuresis in animal model. However, the poor solubility and low bioavailability limited its further development. To overcome these shortcomings, the structure modification of thienoquinoline was carried out in this study, which led to the discovery of novel thienopyridine derivatives as specific urea transporter inhibitors. Further optimization obtained the promising preclinical candidate 8n with not only excellent inhibition effect on urea transporters and diuretic activity on rat model, but also suitable water solubility and Log P value.

KEYWORDS:

Diuretics; Structure-activity relationship; Thienopyridine; Thienoquinoline; Urea transporter inhibitor

PMID:
30959323
DOI:
10.1016/j.ejmech.2019.03.060
[Indexed for MEDLINE]

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