Vericiguat, discovered at Bayer, is the first soluble guanylate cyclase (sGC) stimulator. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Riociguat is a potent, oral stimulator of soluble guanylate cyclase (sGC). It is the first member of a novel class of compounds, being developed by Bayer as an investigational, oral treatment to target a key molecular mechanism underlying pulmonary hypertension (PH). Riociguat demonstrated robust clinical efficacy in two separate PH indications: chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension(PAH). Riociguat works in two ways: it sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding and directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. Through this unique way of working, riociguat decreases blood pressure within the pulmonary arteries that take blood from the heart to the lungs, reducing pressure on the heart leading to improved patient outcomes.

Pentaerythritol tetranitrate is an organic nitrate that has been used for the treatment of angina pectoris. Upon administration, the drug undergoes exstensive metabolism to NO which causes vasodilation and the relaxation of smooth muscle cells. The compound belongs to a familiy of explosive substances and may be used accordingly.

Lificiguat (YC-1) [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole], a chemically synthetic benzylindazole compound, is a direct soluble guanylate cyclase activator. It possessed antiplatelet activity. YC-1 inhibits Hypoxia-inducible factor-1 (HIF-1). YC-1 demonstrated antineoplastic potential both in vitro and in vivo in animal models.

Ataciguat is a novel anthranilic acid derivative that belongs to a new structural class of sGC activators which are capable of activating the oxidized form of sGC. Ataciguat, a nitric oxide-independent soluble guanylate cyclase activator, is being developed by Sanofi (previously sanofi-aventis), in collaboration with Mayo Clinic and National Center for Advancing Translational Sciences. Ataciguat is in phase II clinical trials for the treatment of aortic valve stenosis. It had been used to treat neuropathic pain and peripheral arterial disease, but this research has been discontinued.

Nelociguat, a soluble guanylate cyclase (sGC) activator, has been in phase II clinical trials by Bayer for the treatment of erectile dysfunction and heart failure. However, no recent development has been reported. Nelociguat is a direct soluble guanylate cyclase (sGC) stimulator that acts independently of nitric oxide (NO); has an EC50 of 353 nM on P-VASP formation in rat aortic smooth muscle cells. BAY 60-4552 is pharmacologically active major metabolite of Riociguat.

Cinaciguat acts specifically on oxidized/haem-free soluble guanylyl cyclase by binding to the enzyme's haem pocket and mimicking the nitric-oxide-bound haem group. It is in clinical development for the treatment of acute decompensated heart failure. Cinaciguat had been in phase II clinical trials. However, trials were terminated early because of an excess of hypotension in the cinaciguat arms and subsequent slow enrolment.

BAY 41-8543 (2-[1-[(2-fuorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5(4-morpholinyl)-4,6-pyrimidinediamine) is s potent nitric oxide (NO)-independent stimulator of soluble guanylate cyclase (sGC). BAY 41-8543 manifested both antiplatelet effect and vasodilatation. It has the potential of being a unique clinical utility for the treatment of cardiovascular diseases.

BAY-41-2272 is a direct and NO-independent soluble guanylate cyclase (sGC) stimulator. It sensitizes sGC to nitric oxide (NO), its physiological stimulator, and contains antiplatelet activity. BAY-41-2272 is an inhibitor of GCS. BAY-41-2272 inhibits platelet aggregation (IC50 = 36 nM) and phenylephrine-induced contractions of rabbit aorta (IC50 = 0.30 uM). BAY-41-2272 also reduces vascular smooth muscle growth through cAMP- and cGMP-dependent PKA and PKG pathways. BAY-41-2272 not only sensitized NO-sensitive GC toward activation by NO but also, with comparable potency, inhibited cGMP degradation by PDE5. BAY-41-2272 may provide a novel therapeutic compound for treating chronic hypoxic pulmonary hypertension.