Discovery of novel diarylamides as orally active diuretics targeting urea transporters.

Autor:	Zhang S; 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., Zhao Y; State 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, China., Wang S; 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., Li M; 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., Xu Y; 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., Ran J; Department of Anatomy and Neuroscience Center, Chongqing Medical University, Chongqing 400016, China., Geng X; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China., He J; 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., Meng J; 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., Shao G; 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., Zhou H; 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., Ge Z; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.; School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Chen G; Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA., Li R; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.; School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Yang B; 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.
Jazyk:	angličtina
Zdroj:	Acta pharmaceutica Sinica. B [Acta Pharm Sin B] 2021 Jan; Vol. 11 (1), pp. 181-202. Date of Electronic Publication: 2020 Jun 14.
DOI:	10.1016/j.apsb.2020.06.001
Abstrakt:	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. (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
Databáze:	MEDLINE
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