Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation
of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger
cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through
activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic
Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various
physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter
delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial
Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical
applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator
potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy
(DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease
(SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies
of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in
the near future.