Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure
Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure
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DOI：
10.1007/164_2016_100
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发表时间：
2017-01-01
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影响因子：
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通讯作者：
Lewis, Kelly S.
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作者：
Breitenstein, Stefanie;Roessig, Lothar;Lewis, Kelly S.
随着人口老龄化，心力衰竭（HF）的负担在全球范围内增加，射血分数降低的心力衰竭（HFrEF）和射血分数保留的心力衰竭（HFpEF）的医疗需求均未得到满足。一氧化氮（NO）通路是心血管系统中的关键调节因子，调节血管张力和心肌性能。内皮功能障碍导致的NO-环磷酸鸟苷（cGMP）信号传导轴的破坏和cGMP形成受损可能导致血管紧张素调节异常、血管和心室硬化、纤维化和肥大，从而导致心脏和肾脏功能下降。因此，NO-cGMP途径是心力衰竭的治疗靶点。外源性NO供体如硝酸盐长期以来一直用于治疗心血管疾病，但被证明受到氧化应激和耐受性增加的限制。最近，发现了通过靶向NO受体可溶性鸟苷酸环化酶（sGC）来增强cGMP产生的新型药物。这些化合物，所谓的sGC刺激剂和sGC激活剂，能够增加sGC的酶活性，产生cGMP独立于NO，并已开发出针对这一重要的信号级联在心血管系统中，本文将重点介绍sGC在心血管（CV）的生理和疾病的作用和药理潜力的sGC刺激剂和sGC激活剂在其中。将对临床前数据进行审查和总结，并将提供riociguat和vericiguat（新型直接sGC刺激剂）的可用临床数据。Vericiguat目前正在III期临床项目中进行研究，用于治疗射血分数降低的心力衰竭（HFrEF）。
The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).