Discovery of novel diarylamides as orally active diuretics targeting urea transporters

• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（1）
• 所属期刊栏目: Original articles
• 页码范围: 181-202
• 页数: 22页
• 语种: 英文

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 diuretics.Thus,UT inhibitors are prom-ising 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 identifi-cation 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 inhib-itory concentrations of 1H against UT-B in mouse,rat,and human erythrocyte were 1.60,0.64,and 0.13 pmol/L,respectively.Further investigation suggested that 8 pmol/L 1H more powerfully inhibited UT-Al 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.