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 scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, -[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (), with excellent UT inhibitory activity at the submicromolar level The half maximal inhibitory concentrations of 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 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 at a dose of 100 mg/kg showed superior diuretic effect without causing electrolyte imbalance in rats. Additionally, did not exhibit apparent toxicity and , and possessed favorable pharmacokinetic characteristics. shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.