Urea transporters (UTs) play a vital role in the mechanism of urine concentration and are recognized as new targets for the development of salt-saving diuretics. Therefore, UT inhibitors promise development as new diuretics.
In this study, the authors discovered a new UT inhibitor with a diarylamide scaffold by high-throughput screening. Optimization of inhibitors led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro inhibitory activity of UT at the submicromolar level. Half of the maximal 1H inhibitory concentration against UT-B in mouse, rat, and human erythrocytes was 1.60, 0.64, and 0.13 μmol / L.
Further investigation suggested that 8 μmol / L 1H more strongly inhibited UT-A1 at a rate of 86.8% of UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, the authors first discovered that oral administration of 1H at a dose of 100 mg / kg showed a superior diuretic effect in vivo without causing electrolyte imbalance in rats. In addition, 1H did not show apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a new diuretic for the treatment of hyponatremia accompanied by volume expansion and may cause several side effects.
Acta Pharmaceutica Sinica B
Zhang, S., and others. (2021) Discovery of new diarylamides as orally active diuretics targeting urea transporters. Acta Pharmaceutica Sinica B. doi.org/10.1016/j.apsb.2020.06.001.