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Chemical Structure| 625115-55-1 Chemical Structure| 625115-55-1
Chemical Structure| 625115-55-1

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CAS No.: 625115-55-1

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Riociguat is an oral stimulator of soluble guanylate cyclase (sGC) used to treat pulmonary hypertension.

Synonyms: BAY 632521

4.5 *For Research Use Only !

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Cao, Xuehong ; Zhang, Yali ; Tripp, Audrey Elisabeth ; Steinhauer, Rachael ; Liu, Peiwen ; Aronovitz, Mark , et al.

Abstract: Background: Type-II diabetes (DMII) and metabolic syndrome increase ventricular arrhythmia and sudden cardiac death risk. Objectives: To identify signaling mechanisms through which DMII and metabolic syndrome promote ventricular tachycardia (VT). Methods: We performed ventricular programmed stimulation on leptin receptor mutant (Db/Db) mice with DMII, high fat high sucrose (HFHS)-fed mice with metabolic syndrome, and cGMP-dependent Protein Kinase 1α (PKG1α) leucine zipper mutant (LZM) mice, which do not have DMII or metabolic syndrome but have disrupted PKG1α signaling. Results: During ventricular programmed stimulation, Db/Db and HFHS-fed mice displayed increased VT and T-wave alternans. Cardiomyocytes from these mice displayed early afterdepolarizations. Both models demonstrated decreased heart rate response to parasympathetic inhibition, indicating autonomic dysfunction. cGMP, which mediates cardiac parasympathetic stimulation, was reduced in LVs of Db/Db and HFHS-fed mice. Conversely, cGMP augmentation with soluble guanylate cyclase stimulation (riociguat) or phosphodiesterase 5 inhibition (sildenafil) reduced VT inducibility. PKG1α LZM mice had normal autonomic responsiveness, but excess VT inducibility. Db/Db, HFHS, and LZM mice each demonstrated hyperactivated myocardial glycogen synthase kinase3β (GSK3β). Further, GSK3β inhibition with TWS119 abolished inducible VT in these mice. Diastolic cytosolic Ca2+ reuptake slope decreased in cardiomyocytes from all models, while GSK3β inhibition with TWS119 reversed this effect. Phospholamban (PLB), which inhibits sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a-mediated Ca2+ reuptake, was hyperactivated/hypophosphorylated in HFHS-fed and LZM mice, and this was reversed by TWS119. Conclusions: These findings identify cGMP reduction as driving GSK3β hyperstimulation, calcium dyshomeostasis, and VT in DMII and metabolic syndrome. Pharmacological modulation of these pathways opposes VT pathogenesis.

Keywords: Ventricular tachycardia ; Diabetes ; Arrhythmia ; cGMP ; GSK3β ; Autonomic dysfunction

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Marcel Kremser ;

Abstract: Autoimmune hemolysis is a condition characterized by platelet activation and thrombotic complications, offering limited treatment options. In recent years, the role of ferroptosis, a regulated cell death caused by lipid peroxidation and reactive oxygen species, has been investigated in platelets. It has been found that hemin, a byproduct of hemolysis, can trigger ferroptosis in platelets. Exploring the mechanisms behind ferroptosis in platelets and its connection to autoimmune hemolysis holds promising potential for developing targeted therapies to reduce thrombotic risk in affected patients. A key player in this context is the modulation of the cyclic guanosine monophosphate (cGMP) signaling pathway. In the experiments conducted with platelets from patients and healthy controls, it was observed that plasma samples from patients exhibited increased platelet aggregation, particularly under ADP stimulation. Treatment with cGMP modulators reduced aggregation in patient platelets, emphasizing the importance of cGMP modulation in reducing platelet activation in hemolytic plasma. Direct treatment of platelets with hemin resulted in enhanced platelet activation, manifested by increased surface expression of P-selectin, fibrinogen binding, ATP release, and morphological changes. cGMP modulation significantly attenuated these effects. Additionally, it was found that cGMP regulates hemin-induced ferroptosis in platelets, as demonstrated by phosphatidylserine exposure, ROS activity, and reduced mitochondrial membrane potential. Examination of the platelet lipidome revealed concentration-dependent changes due to hemin and the modulating effect of DEA/NO and riociguat on platelet lipidome. Analysis of ferroptosis-related lipids underscores their central role in the ferroptosis signaling pathway. The study provides insights into the prothrombotic properties of hemolytic plasma and the interaction of hemin, platelet activation, and cGMP modulation. Modulation of the cGMP signaling pathway shows promising inhibitory effects on platelet activation in autoimmune hemolysis. Further research is needed to clarify the underlying mechanisms and explore clinical applications of cGMP modulation.

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Alternative Products

Product Details of Riociguat

CAS No. :625115-55-1
Formula : C20H19FN8O2
M.W : 422.42
SMILES Code : O=C(OC)N(C1=C(N)N=C(C2=NN(CC3=CC=CC=C3F)C4=NC=CC=C42)N=C1N)C
Synonyms :
BAY 632521
MDL No. :MFCD19443708
InChI Key :WXXSNCNJFUAIDG-UHFFFAOYSA-N
Pubchem ID :11304743

Safety of Riociguat

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Related Pathways of Riociguat

GPCR

Isoform Comparison

Biological Activity

In Vitro:

Cell Line
Concentration Treated Time Description Reference
human podocytes 20 μM 15 minutes Riociguat stimulated cGMP synthesis, decreased Adriamycin-induced TRPC6 expression, inhibited TRPC6-mediated Ca2+ influx, and reduced podocyte injury. PMC8621407

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description Reference
Mice Adriamycin-induced nephropathy model intravenous injection 10.5 mg/kg single injection, duration of 14 days In eNOS knockout mice, Adriamycin-induced nephropathy led to increased glomerular TRPC6 expression, indicating that NO protects podocytes by inhibiting TRPC6 expression in vivo. PMC8621407

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT04954742 Primary Pulmonary Arterial Hyp... More >>ertension|Chronic Thromboembolic Pulmonary Hypertension Less << PHASE4 RECRUITING 2025-03-26 Centre for Pulmonary Hypertens... More >>ion at the Thoraxklinik Heidelberg, Heidelberg University Hospital, Heidelberg, 69126, Germany Less <<
NCT02024386 Hypertension, Pulmonary|Altitu... More >>de Sickness Less << PHASE4 COMPLETED 2025-12-15 Duke Center for Hyperbaric Med... More >>icine and Environmental Physiology, Trent Drive, Building CR2, Room 0584, Box 3823,, Durham, North Carolina, 27710, United States Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.37mL

0.47mL

0.24mL

11.84mL

2.37mL

1.18mL

23.67mL

4.73mL

2.37mL
Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

References

[1]Mittendorf J, Weigand S, et al. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem. 2009 May;4(5):853-65.

[2]Schermuly RT, Stasch JP, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008 Oct;32(4):881-91.

[3]Chamorro V, Morales-Cano D, et al. Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching. PLoS One. 2018 Jan 24;13(1):e0191239.

[4]Lang M, Kojonazarov B, et al. The soluble guanylate cyclase stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PLoS One. 2012;7(8):e43433.

[5]Rai N, Veeroju S, et al. Effect of Riociguat and Sildenafil on Right Heart Remodeling and Function in Pressure Overload Induced Model of Pulmonary Arterial Banding. Biomed Res Int. 2018 Jan 3;2018:3293584.

[6]BAY 63-2521

[7]Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, Kern A, Knorr A, Lang D, Muenter K, Radtke M, Schirok H, Schlemmer KH, Stahl E, Straub A, Wunder F, Stasch JP. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem. 2009 May;4(5):853-65. doi: 10.1002/cmdc.200900014. PMID: 19263460.

[8]Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Müller D, Schlüter KD, Dingendorf A, Hackemack S, Kolosionek E, Kaulen C, Dumitrascu R, Weissmann N, Mittendorf J, Klepetko W, Seeger W, Ghofrani HA, Grimminger F. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008 Oct;32(4):881-91. doi: 10.1183/09031936.00114407. Epub 2008 Jun 11. PMID: 18550612.

 

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