Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, A-1090 Vienna, Austria.
Independent Researcher, A-1180 Vienna, Austria.
Int J Mol Sci. 2023 Apr 24;24(9):7775. doi: 10.3390/ijms24097775.
Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.
上皮钠离子通道（ENaC）是相互作用的生化途径复杂网络的一部分，因此涉及多种疾病状态。根据突变的部位和类型，会产生功能获得或功能丧失的症状，这些症状从无症状到危及生命的疾病，如李氏综合征、囊性纤维化或广义假性醛固酮增多症 1 型。与疾病相关的 ENaC 变体有助于进一步了解其分子机制，以便为特定的药物靶向创建模型。ENaC 调节剂的鉴定和表征不仅有助于我们深入了解这些调节过程如何相互作用，而且还能够发现由 ENaC 功能障碍引起的疾病的新治疗靶点。许多测试化合物在体外和动物模型中显示出令人鼓舞的结果，但在临床环境中则较少。EMA 和 FDA 指定的孤儿药物 solnatide 目前正在急性呼吸窘迫综合征的 2 期临床试验中进行测试，NOX1/NOX4 抑制剂 setanaxib 正在进行 2 期和 3 期临床试验，用于原发性胆汁性胆管炎、肝硬度和癌的治疗。已确立的 ENaC 阻滞剂氨氯吡咪主要用作耐药性高血压的附加药物，并正在进行正在进行的 3 期和 4 期临床试验，以用于特殊应用。本文综述集中讨论了寻找新型治疗剂的一些最新进展。
