Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany.
Institute of Pharmacology, Hannover Medical School, Hanover, Germany.
Br J Pharmacol. 2024 Nov;181(21):4130-4151. doi: 10.1111/bph.15698. Epub 2021 Dec 1.
The discovery of soluble GC (sGC) stimulators and sGC activators provided valuable tools to elucidate NO-sGC signalling and opened novel pharmacological opportunities for cardiovascular indications and beyond. The first-in-class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure. sGC stimulators enhance sGC activity independent of NO and also act synergistically with endogenous NO. The sGC activators specifically bind to, and activate, the oxidised haem-free form of sGC. Substantial research efforts improved on the first-generation sGC activators such as cinaciguat, culminating in the discovery of runcaciguat, currently in clinical Phase II trials for chronic kidney disease and diabetic retinopathy. Here, we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In the future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential.
可溶性鸟苷酸环化酶（sGC）刺激剂和 sGC 激活剂的发现为阐明 NO-sGC 信号提供了有价值的工具，并为心血管疾病及其他疾病的治疗开辟了新的药理学机会。首个 sGC 刺激剂利奥西呱于 2013 年被批准用于肺动脉高压，而维立西呱则于最近被批准用于心力衰竭。sGC 刺激剂可增强 sGC 活性，且不依赖于一氧化氮，还可与内源性一氧化氮协同作用。sGC 激活剂特异性结合并激活 sGC 氧化型无血红素形式。大量的研究工作改进了第一代 sGC 激活剂，如西那卡塞，最终发现了鲁西卡塞，目前正在进行慢性肾脏病和糖尿病性视网膜病变的临床 II 期试验。本文重点介绍 sGC 刺激剂和 sGC 激活剂的发现和开发、它们独特的作用模式、临床前特征和临床研究。未来，我们预计会有更多的 sGC 激动剂用于新的适应证，这反映了它们独特的治疗潜力。
