Discovery and development of sGC stimulators for the treatment of pulmonary hypertension and rare diseases

The NO/sGC/cGMP signaling cascade plays a pivotal role in regulation of cardiovascular, cardiopulmonary and cardiorenal diseases and impairment of this cascade results in severe pathologies. Therefore, pharmacological interventions, targeting this pathway are promising strategies for treating a variety of diseases. Nitrates, supplementing NO and, PDE5 inhibitors preventing cGMP degradation, are used for angina pectoris treatment and the treatment of pulmonary arterial hypertension (PAH), respectively. More recently, a new class of drugs which directly stimulate the sGC enzyme and trigger NO-independent cGMP production was introduced and termed sGC stimulators. In 2013, the first sGC stimulator, riociguat, was approved for the treatment of PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Since cGMP targets multiple intracellular downstream targets, sGC stimulators have shown - beyond the well characterized vasodilatation - anti-fibrotic, anti-inflammatory and anti-proliferative effects. These additional modes of action might extend the therapeutic potential of this drug class substantially. This review summarizes the NO/sGC/cGMP signaling cascades, the discovery and the mode of action of sGC stimulators. Furthermore, the preclinical evidence and development of riociguat for the treatment of PAH and CTEPH is reviewed. Finally, a summary of the antifibrotic effects of sGC stimulators, especially the most recent finding for skin fibrosis are included which may indicate efficacy in fibrotic diseases like Systemic Sclerosis (SSc).