Discovery of novel diarylamides as orally active diuretics targeting urea transporters
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 scaf...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383520305943 |
| _version_ | 1818656681401253888 |
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| author | Shun Zhang Yan Zhao Shuyuan Wang Min Li Yue Xu Jianhua Ran Xiaoqiang Geng Jinzhao He Jia Meng Guangying Shao Hong Zhou Zemei Ge Guangping Chen Runtao Li Baoxue Yang |
| author_facet | Shun Zhang Yan Zhao Shuyuan Wang Min Li Yue Xu Jianhua Ran Xiaoqiang Geng Jinzhao He Jia Meng Guangying Shao Hong Zhou Zemei Ge Guangping Chen Runtao Li Baoxue Yang |
| author_sort | Shun Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T03:29:27Z |
| format | Article |
| id | doaj.art-77e2f8c4840745bca951aaa056d16e97 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-17T03:29:27Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-77e2f8c4840745bca951aaa056d16e972022-12-21T22:05:18ZengElsevierActa Pharmaceutica Sinica B2211-38352021-01-01111181202Discovery of novel diarylamides as orally active diuretics targeting urea transportersShun Zhang0Yan Zhao1Shuyuan Wang2Min Li3Yue Xu4Jianhua Ran5Xiaoqiang Geng6Jinzhao He7Jia Meng8Guangying Shao9Hong Zhou10Zemei Ge11Guangping Chen12Runtao Li13Baoxue Yang14Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaDepartment of Anatomy and Neuroscience Center, Chongqing Medical University, Chongqing 400016, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, ChinaState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; School of Pharmaceutical Sciences, Peking University, Beijing 100191, ChinaDepartment of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USAState Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Corresponding authors. Tel./fax: +86 10 82805954 (Runtao Li), +86 10 82805622 (Baoxue Yang)Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China; Corresponding authors. Tel./fax: +86 10 82805954 (Runtao Li), +86 10 82805622 (Baoxue Yang)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.http://www.sciencedirect.com/science/article/pii/S2211383520305943Urea transporter inhibitorDiureticStructure optimizationOral administration |
| spellingShingle | Shun Zhang Yan Zhao Shuyuan Wang Min Li Yue Xu Jianhua Ran Xiaoqiang Geng Jinzhao He Jia Meng Guangying Shao Hong Zhou Zemei Ge Guangping Chen Runtao Li Baoxue Yang Discovery of novel diarylamides as orally active diuretics targeting urea transporters Acta Pharmaceutica Sinica B Urea transporter inhibitor Diuretic Structure optimization Oral administration |
| title | Discovery of novel diarylamides as orally active diuretics targeting urea transporters |
| title_full | Discovery of novel diarylamides as orally active diuretics targeting urea transporters |
| title_fullStr | Discovery of novel diarylamides as orally active diuretics targeting urea transporters |
| title_full_unstemmed | Discovery of novel diarylamides as orally active diuretics targeting urea transporters |
| title_short | Discovery of novel diarylamides as orally active diuretics targeting urea transporters |
| title_sort | discovery of novel diarylamides as orally active diuretics targeting urea transporters |
| topic | Urea transporter inhibitor Diuretic Structure optimization Oral administration |
| url | http://www.sciencedirect.com/science/article/pii/S2211383520305943 |
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