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Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Acta Pharmaceutica Sinica B 2021年第1期11卷 181-202页

作者： 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 Department of Pharmacology School of Basic Medical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100191China Key Laboratory of Molecular Cardiovascular Sciences Ministry of EducationBeijing 100191China School of Pharmaceutical Sciences Peking UniversityBeijing 100191China College of Pharmacy Inner Mongolia Medical UniversityHohhot 010110China Department of Anatomy and Neuroscience Center Chongqing Medical UniversityChongqing 400016China Department of Physiology Emory University School of MedicineAtlantaGA 30322USA

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 ***,UT inhibitors are promising for development as novel *** the present study,a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput *** of the inhibitor led to the identifi-cation of a promising preclinical candidate,N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide(1 H),with excellent in vitro UT inhibitory activity at the submicromolar *** half maximal inhibitory concentrations of 1 H against UT-B in mouse,rat,and human erythrocyte were 1.60,0.64,and0.13 mmol/L,*** investigation suggested that 8 mmol/L 1 H more powerfully inhibited UT-A1 at a rate of 86.8%than UT-B at a rate of 73.9%in MDCK cell *** interestingly,we found for the first time that oral administration of 1 H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in ***,1 H did not exhibit apparent toxicity in vivo and in vitro,and possessed favorable pharmacokinetic characteristics.1 H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

关键词： urea transporter inhibitor Diuretic Structure optimization Oral administration

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