sGC

Riocigua works through a haem-dependent but NO-independent mechanism to stimulate the recombinant sGC concentration dependently from 0.1 to 100 μM with an effect ranging from two to 73 times[1]. Riociguat has no direct effects on the contractility and relaxation of cardiac myocytes, but it inhibits platelet function in washed platelets but not in whole blood[2].

Riociguat (10 mg/kg/d, p.o.) partially reverses the pulmonary arterial hypertension, the hypertrophy of the right heart, and the structural remodeling of the lung vasculature in chronic treatment of hypoxic mice and MCT-injected rats[1].

Mice: Four groups of mice are used for the chronic intervention studies: ten control mice exposed to normoxic gas for 35 days; ten hypoxic gas exposed for 21 days; ten mice exposed for 35 days and given the vehicle (2% methylcellulose solution) from day 21 to day 35; and ten mice exposed for 35 days and given BAY 63-2521 (10 mg/kg) once daily by oral application from day 21 to day 35. In order to perform continuous radiotelemetry measurements of cardiac frequency and Prvs, a different group of mice is given oral application of BAY 63-2521 (10 mg/kg) once daily from day 21 to day 35 after being exposed to hypoxic gas for 35 days. Further two groups of animals are studied: control mice (n = 12) and animals exposed to hypoxia for 21 days (n = 12) in order to examine vascular reactivity in isolated mouse lungs. Rats: One week following MCT injection, rats are randomly assigned to receive chronic BAY 63-2521 treatment. A vehicle (2% methylcellulose solution) or BAY 63-2521 (10 mg/kg) are administered orally to rats in the experimental groups once daily. On day 35, rats undergo histological evaluation and are monitored every day for the duration of their lives.

Absorption, Distribution and Excretion
The pharmacokinetics of riociguant are dose proportional from 0.5 mg to 2.5 mg. The absolute bioavailability is approximately 94%. After oral administration, peak plasma concentrations were achieved within 1.5 hours. Food does not affect the bioavailability of riociguat.
Riociguat is eliminated in the urine (40%) and feces (53%), largely as metabolites.
Volume of distribution at steady state = 30 L

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Metabolism / Metabolites
The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

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Biological Half-Life
About 12 hours in patients and 7 hours in healthy subjects.

Hepatotoxicity
In preregistration studies, riociguat was not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. Since approval of riociguat, there have been no published reports of hepatotoxicity, and the product label does not mention liver injury as an adverse event.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of riociguat during breastfeeding. The manufacturer recommends that breastfeeding be avoided during riociguat use. The drug should be absent from breastmilk 3 days after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
95% with serum albumin and alpha-1–acidic glycoprotein being the main binding components.

[1]. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008 Oct;32(4):881-91.

[2]. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs. 2011 Apr;20(4):567-76.

[3]. Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth. PLoS One. 2018 Jul 10;13(7):e0199927.

Riociguat is a carbamate ester that is the methyl ester of {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamic acid. It is used for treatment of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension It has a role as a soluble guanylate cyclase activator and an antihypertensive agent. It is a pyrazolopyridine, an aminopyrimidine, an organofluorine compound and a carbamate ester.
Riociguat is a soluble guanylate cyclase (sGC) agonist approved in the USA, Europe and several other regions for patients with group I PAH (pulmonary arterial hypertension) in WHO FC II or III; and for the treatment of patients with inoperable CTEPH (chronic thromboembolic pulmonary hypertension), or persistent/recurrent PH (pulmonary hypertension) after pulmonary endarterectomy in WHO FC II or III. Riociguat is marketed under the brand Adempas® by Bayer HealthCare Pharmaceuticals. Treatment with riociguat costs USD $7,500 for 30 days of treatment.
Riociguat is a Soluble Guanylate Cyclase Stimulator. The mechanism of action of riociguat is as a Guanylate Cyclase Stimulator.
Riociguat is a stimulator of guanylate cyclase which causes relaxation of vascular smooth muscle and is used to treat severe pulmonary arterial hypertension. Riociguat has not been linked to significant serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury.

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Drug Indication
Riociguat is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. Riociguat is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Riociguat monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).
FDA Label
Chronic thromboembolic pulmonary hypertension (CTEPH)Adempas is indicated for the treatment of adult patients with WHO Functional Class (FC) II to III withinoperable CTEPH,persistent or recurrent CTEPH after surgical treatment,to improve exercise capacity. Pulmonary arterial hypertension (PAH)AdultsAdempas, as monotherapy or in combination with endothelin receptor antagonists, is indicated for the treatment of adult patients with pulmonary arterial hypertension (PAH) with WHO Functional Class (FC) II to III to improve exercise capacity. Efficacy has been shown in a PAH population including aetiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease. PaediatricsAdempas is indicated for the treatment of PAH in paediatric patients aged less than 18 years of age and body weight ≥ 50 kg with WHO Functional Class (FC) II to III in combination with endothelin receptor antagonists.  
Treatment of pulmonary hypertension

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Mechanism of Action
Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also 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.

C20H19FN8O2

422.42

422.161

C, 56.87; H, 4.53; F, 4.50; N, 26.53; O, 7.58

625115-55-1

Riociguat-13C,d6

11304743

Light yellow solid powder

1.5±0.1 g/cm3

567.2±50.0 °C at 760 mmHg

296.8±30.1 °C

0.0±1.6 mmHg at 25°C

1.720

-0.31

2

9

5

31

618

0

FC1=CC=CC=C1CN2C3=NC=CC=C3C(C4=NC(N)=C(C(N)=N4)N(C)C(OC)=O)=N2

WXXSNCNJFUAIDG-UHFFFAOYSA-N

InChI=1S/C20H19FN8O2/c1-28(20(30)31-2)15-16(22)25-18(26-17(15)23)14-12-7-5-9-24-19(12)29(27-14)10-11-6-3-4-8-13(11)21/h3-9H,10H2,1-2H3,(H4,22,23,25,26)

methyl N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-N-methylcarbamate

Riociguat; BAY 63-2521; BAY63-2521; BAY632521; Trade name: Adempas

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.92 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)