Discovery of novel diarylamides as orally active diuretics targeting urea transporters

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 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 Cheng;Runtao Li;Baoxue Yang

作者机构：Department of PharmacologySchool of Basic Medical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic DrugsPeking UniversityBeijing 100191China Key Laboratory of Molecular Cardiovascular SciencesMinistry of EducationBeijing 100191China School of Pharmaceutical SciencesPeking UniversityBeijing 100191China College of PharmacyInner Mongolia Medical UniversityHohhot 010110China Department of Anatomy and Neuroscience CenterChongqing Medical UniversityChongqing 400016China Department of PhysiologyEmory University School of MedicineAtlantaGA 30322USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第1期

页      面：181-202页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by National Natural Science Foundation of China(Grant Nos.81620108029,81974083,and 81330074) Beijing Natural Science Foundation grant 7172113(China) 

主　　题：Urea transporter inhibitor Diuretic Structure optimization Oral administration 

摘      要：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.