Department of Medicinal Chemistry, National University of Pharmacy, 53 Pushkinska Str., 61002, Kharkiv, Ukraine.
Department of General, Bioinorganic, Physical and Colloidal Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Str., 79010, Lviv, Ukraine.
Eur J Med Chem. 2020 Dec 15;208:112855. doi: 10.1016/j.ejmech.2020.112855. Epub 2020 Sep 19.
Diuretics are the first-line therapy for widespread cardiovascular and non-cardiovascular diseases. Traditional diuretics are commonly prescribed for treatment in patients with hypertension, edema and heart failure, as well as with a number of kidney problems. They are diseases with high mortality, and the number of patients suffering from heart and kidney diseases is increasing year by year. The use of several classes of diuretics currently available for clinical use exhibits an overall favorable risk/benefit balance. However, they are not devoid of side effects. Hence, pharmaceutical researchers have been making efforts to develop new drugs with a better pharmacological profile. High-throughput screening, progress in protein structure analysis and modern methods of chemical modification have opened good possibilities for identification of new promising agents for preclinical and clinical testing. In this review, we provide an overview of the medicinal chemistry approaches toward the development of small molecule compounds showing diuretic activity that have been discovered over the past decade and are interesting drug candidates. We have discussed promising natriuretics/aquaretics/osmotic diuretics from such classes as: vasopressin receptor antagonists, SGLT2 inhibitors, urea transporters inhibitors, aquaporin antagonists, adenosine receptor antagonists, natriuretic peptide receptor agonists, ROMK inhibitors, WNK-SPAK inhibitors, and pendrin inhibitors.
利尿剂是广泛的心血管和非心血管疾病的一线治疗药物。传统的利尿剂通常用于治疗高血压、水肿和心力衰竭患者，以及一些肾脏问题。这些疾病的死亡率很高，患有心脏和肾脏疾病的患者人数逐年增加。目前临床使用的几类利尿剂总体上表现出良好的风险/效益平衡。然而，它们并非没有副作用。因此，制药研究人员一直在努力开发具有更好药理学特性的新药。高通量筛选、蛋白质结构分析的进展和现代化学修饰方法为鉴定新的有前途的药物候选物用于临床前和临床测试提供了良好的可能性。在这篇综述中，我们概述了过去十年中发现的具有利尿活性的小分子化合物的药物化学方法，这些化合物是很有前途的候选药物。我们讨论了来自以下几类的有前途的利钠肽/水通道蛋白/渗透利尿剂：血管加压素受体拮抗剂、SGLT2 抑制剂、尿素转运体抑制剂、水通道蛋白拮抗剂、腺苷受体拮抗剂、利钠肽受体激动剂、ROMK 抑制剂、WNK-SPAK 抑制剂和 pendrin 抑制剂。
