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首页> 外文期刊>Biological chemistry >From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators
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From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators

机译：从分子到患者：探索可溶性胍基环化酶刺激器的治疗作用

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Nitric oxide (NO) signaling represents one of the major regulatory pathways for cardiovascular function. After the discovery of NO, awarded with the Nobel Prize in 1998, this signaling cascade was stepwise clarified. We now have a good understanding of NO production and NO downstream targets such as the soluble guanylyl cyclases (sGCs) which catalyze cGMP production. Based on the important role of NO-signaling in the cardiovascular system, intense research and development efforts are currently ongoing to fully exploit the therapeutic potential of cGMP increase. Recently, NO-independent stimulators of sGC (sGC stimulators) were discovered and characterized. This new compound class has a unique mode of action, directly binding to sGC and triggering cGMP production. The first sGC stimulator made available to patients is riociguat, which was approved in 2013 for the treatment of different forms of pulmonary hypertension (PH). Besides riociguat, other sGC stimulators are in clinical development, with vericiguat in phase 3 clinical development for the treatment of chronic heart failure (HF). Based on the broad impact of NO/cGMP signaling, sGC stimulators could have an even broader therapeutic potential beyond PH and HF. Within this review, the NO/sGC/cGMP/PKG/PDE-signaling cascade and the major pharmacological intervention sites are described. In addition, the discovery and mode of action of sGC stimulators and the clinical development in PH and HF is covered. Finally, the preclinical and clinical evidence and treatment approaches for sGC stimulators beyond these indications and the cardiovascular disease space, like in fibrotic diseases as in systemic sclerosis (SSc), are reviewed.
机译：一氧化氮（NO）信号传导代表心血管功能的主要调节途径之一。在1998年获得诺贝尔奖的授予诺贝尔奖后，这一信令级联逐步澄清。我们现在对催化CGMP生产的可溶性观光伴侣（SGCS）具有良好的生产和没有下游目标。基于无信令在心血管系统中的重要作用，目前正在进行激烈的研究和开发工作，以充分利用CGMP增加的治疗潜力。最近，发现并表征了SGC（SGC刺激器）的无关刺激器。这个新的复合类具有独特的动作模式，直接绑定到SGC并触发CGMP生产。可用于患者的第一个SGC刺激器是RIOCIGUAT，其于2013年批准用于治疗不同形式的肺动脉高压（pH）。除Riociguat外，其他SGC刺激器还在临床开发中，vericiguat在第3期临床开发中治疗慢性心力衰竭（HF）。基于NO / CGMP信号传导的广泛影响，SGC刺激器可具有超越pH和HF的更广泛的治疗潜力。在本次审查中，描述了NO / SGC / CGMP / PKG / PDE信号级联和主要药理学干预网站。此外，SGC刺激器的发现和作用方式和pH和HF在pH和HF中的临床发育。最后，综述了超出这些适应症和心血管疾病空间的SGC刺激器的临床前和临床证据和治疗方法，如在系统性硬化症（SSC）中的纤维化疾病中。

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