Urea transporters (UTs) have been identified as new targets for diuretics. Functional deletion of UTs led to urea-selective urinary concentrating defects with relative salt sparing. In our previous study, a UT inhibitor with a diarylamide scaffold, which is denoted as 11a, was demonstrated as the first orally available UT inhibitor. However, the oral bioavailability of 11a was only 4.38%, which obstructed its clinical application. In this work, by replacing the nitro group of 11a with an acetyl group, 25a was obtained. Compared with 11a, 25a showed a 10 times stronger inhibitory effect on UT-B (0.14 μM vs. 1.41 μM in rats, and 0.48 μM vs. 5.82 μM in mice) and a much higher inhibition rate on UT-A1. Moreover, the metabolic stability both in vitro and in vivo and the drug-like properties (permeability and solubility) of 25a were obviously improved compared with those of 11a. Moreover, the bioavailability of 25a was 15.18%, which was 3 times higher than that of 11a, thereby resulting in significant enhancement of the diuretic activities in rats and mice. 25a showed excellent potential for development as a promising clinical diuretic candidate for targeting UTs to treat diseases that require long-term usage of diuretics, such as hyponatremia.

尿素转运蛋白 (UTs) 已被确定为利尿剂的新靶点。UTs 的功能缺失导致尿素选择性尿浓缩缺陷和相对盐分保留。在我们之前的研究中，一种带有二芳基酰胺支架的 UT 抑制剂，表示为11a，被证明是第一个口服可用的 UT 抑制剂。但11a的口服生物利用度仅为4.38%，阻碍了其临床应用。在这项工作中，通过用乙酰基取代11a的硝基，得到25a 。与11a相比，25a对 UT-B 的抑制作用强 10 倍（大鼠中0.14 μM对1.41 μM，0.48 μM对在小鼠中为 5.82 μM）和对 UT-A1 的抑制率更高。此外，与11a相比， 25a的体内外代谢稳定性和类药性能（渗透性和溶解性）均有明显提高。此外， 25a的生物利用度为15.18%，是11a的3倍，从而导致大鼠和小鼠的利尿活性显着增强。25a显示出作为一种有前途的临床利尿剂候选物的巨大发展潜力，用于靶向 UT 治疗需要长期使用利尿剂的疾病，例如低钠血症。