Reactome | sGC stimulators bind sGC:NO

sGC stimulators bind sGC:NO

Stable Identifier

R-HSA-9620456

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Soluble guanylate cyclase (sGC) modulators are small-molecule drugs that bind sGC and enhance nitric oxide (NO)-mediated cGMP signalling, resulting in vasodilation and inhibition of platelet aggregation. The suffix “ciguat” is the unique identifier for this drug class. There are two types of "ciguats"; NOsGC stimulators, which act through allosteric regulation and NOsGC activators, which occupy the heme binding site and work additively with NO (Kraehling & Sessa 2017).

NOsGC stimulators activate sGC independently of NO. This was demonstrated in human platelets by the first allosteric activator lificiguat (YC-1), a benzyl indazol derivative (Friebe et al. 1998). Lificiguat, synergistically with NO, stimulates sGC activity 200-800 fold to result in inhibition of platelet aggregation. A regulatory site on sGC was discovered to be the probable binding site (C239 and C244 regions) for sGC stimulators using the pyrazolopyridine BAY 41-2272, a lificiguat analog (Stasch et al. 2001). BAY 41-2272 induces vasodilation without developing nitrate tolerance, possesses antiplatelet activity and reduces mortality. Optimisation experiments on lificiguat led to the development of riociguat (BAY 63-252, Adempas). Riociguat, activates NOsGC 70-fold at therapeutic concentrations and is the only "ciguat" so far to be approved for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) (Schermuly et al. 2008).

Another NOsGC stimulator, vericiguat, shows an optimized pharmacokinetic profile and allows a once daily dosing regimen, unlike riociguat (3 times a day) (Breitenstein et al. 2017). Vericiguat is in clinical trials to determine its efficacy in heart failure, in patients with chronic failure and reduced ejection fraction (Gheorghiade et al. 2015). Praliciguat (IW-1973) is a novel clinical-stage NOsGC stimulator under clinical investigation for the treatment of heart failure with preserved ejection fraction and diabetic nephropathy (Tobin et al. 2018, Breitenstein et al. 2017).

Literature References

PubMed ID	Title	Journal	Year
11242081	NO-independent regulatory site on soluble guanylate cyclase Schröder, H, Minuth, T, Pleiss, U, Stahl, E, Stasch, JP, Straub, A, Schramm, M, Steinke, W, Dembowsky, K, Schroeder, W, Apeler, H, Alonso-Alija, C, Perzborn, E, Becker, EM, Gerzer, R, Feurer, A	Nature	2001
9855623	YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets Koesling, D, Schultz, G, Smolenski, A, Friebe, A, Müllershausen, F, Walter, U	Mol. Pharmacol.	1998