Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany.
Department of Pharmacology, Hannover Medical School, Hannover, Germany.
Handb Exp Pharmacol. 2021;264:355-394. doi: 10.1007/164_2018_197.
When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.
当 Furchgott、Murad 和 Ignarro 因发现一氧化氮（NO）而于 1998 年获得诺贝尔生理学或医学奖时，这一发现的治疗意义还无法完全预见。这是因为当时可用的治疗药物，如一氧化氮供体，无法实现持续和持久的环鸟苷酸单磷酸（cGMP）刺激，且治疗窗较窄。如今，20 年过去了，可溶性鸟苷酸环化酶（sGC）刺激剂利奥西呱已上市，是唯一获批用于治疗两种肺动脉高压（PAH/CTEPH）的药物，多种其他 sGC 刺激剂和 sGC 激活剂也处于临床前和临床开发阶段，用于治疗其他适应症。sGC 刺激剂和 sGC 激活剂的发现是一氧化氮/sGC/cGMP 药理学领域的一个里程碑。sGC 刺激剂和 sGC 激活剂分别直接与还原型、血红素结合型和氧化型、无血红素型 sGC 结合，导致 cGMP 产生增加。sGC 刺激剂在血红素结合酶上的作用不依赖于 NO，但在存在 NO 的情况下会增强，而 sGC 激活剂与无血红素型 sGC 相互作用。这些 sGC 刺激和激活的高度创新药理学原理似乎具有非常广泛的治疗潜力。因此，学术界和工业界都在积极开展研究和开发工作，以充分利用这些新型化合物类别的治疗益处。在这里，我们总结了 sGC 刺激剂和 sGC 激活剂的发现以及这两类化合物的最新进展，包括作用机制、化学结构以及术语和命名法的起源。此外，还回顾了探索其体外、离体和体内药理学的多个方面的临床前研究，提供了多种潜在应用的概述。最后，报告了这些化合物在心力衰竭、糖尿病肾病、纤维化疾病和高血压等多种疾病中的治疗潜力的临床研究进展。总之，sGC 刺激剂和 sGC 激活剂具有独特的作用机制，在心血管疾病及其他领域具有广泛的治疗潜力。
