Identification

Name
Riociguat
Accession Number
DB08931
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Methyl N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminate
  • Riociguat
  • Riociguatum
External IDs
BAY 41-2272 / BAY 63-2521 / UNII-RU3FE2Y4XI
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AdempasTablet2 mgOralBayer2013-09-25Not applicableCanada
AdempasTablet, film coated2.5 mg/1OralBayer2013-10-08Not applicableUs
AdempasTablet, film coated2 mgOralBayer Ag2014-03-27Not applicableEu
AdempasTablet, film coated1.5 mgOralBayer Ag2014-03-27Not applicableEu
AdempasTablet0.5 mgOralBayer2013-09-25Not applicableCanada
AdempasTablet, film coated1 mg/1OralBayer2013-10-08Not applicableUs
AdempasTablet, film coated1.5 mgOralBayer Ag2014-03-27Not applicableEu
AdempasTablet, film coated2.5 mgOralBayer Ag2014-03-27Not applicableEu
AdempasTablet, film coated1 mgOralBayer Ag2014-03-27Not applicableEu
AdempasTablet, film coated1 mgOralBayer Ag2014-03-27Not applicableEu
Categories
UNII
RU3FE2Y4XI
CAS number
625115-55-1
Weight
Average: 422.4157
Monoisotopic: 422.161500097
Chemical Formula
C20H19FN8O2
InChI Key
WXXSNCNJFUAIDG-UHFFFAOYSA-N
InChI
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)
IUPAC Name
methyl N-(4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)-N-methylcarbamate
SMILES
COC(=O)N(C)C1=C(N)N=C(N=C1N)C1=NN(CC2=C(F)C=CC=C2)C2=C1C=CC=N2

Pharmacology

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%).

Associated Conditions
Pharmacodynamics
Not Available
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.

TargetActionsOrganism
AGuanylate cyclase soluble subunit alpha-2
agonist
stimulator
Human
Absorption

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.

Volume of distribution

Volume of distribution at steady state = 30 L

Protein binding

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

Metabolism

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

Route of elimination

Riociguat is eliminated in the urine (40%) and feces (53%), largely as metabolites.

Half life

About 12 hours in patients and 7 hours in healthy subjects.

Clearance
Not Available
Toxicity

EMBRYO-FETAL TOXICITY Do not administer Riociguat to a pregnant female because it may cause fetal harm. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception. For all female patients, Riociguat is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Riociguat can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Riociguat.
3-isobutyl-1-methyl-7H-xanthine3-isobutyl-1-methyl-7H-xanthine may increase the hypotensive activities of Riociguat.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Riociguat.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Riociguat.
5-androstenedioneThe metabolism of Riociguat can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Riociguat can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanine6-O-benzylguanine may increase the hypotensive activities of Riociguat.
7-Deazaguanine7-Deazaguanine may increase the hypotensive activities of Riociguat.
7,9-Dimethylguanine7,9-Dimethylguanine may increase the hypotensive activities of Riociguat.
Food Interactions
Not Available

References

Synthesis Reference

"Patent Link":http://www.google.com/patents/US7173037

General References
  1. Soeiro-Pereira PV, Falcai A, Kubo CA, Oliveira-Junior EB, Marques OC, Antunes E, Condino-Neto A: BAY 41-2272, a soluble guanylate cyclase agonist, activates human mononuclear phagocytes. Br J Pharmacol. 2012 Jul;166(5):1617-30. doi: 10.1111/j.1476-5381.2011.01764.x. [PubMed:22044316]
  2. Hambly N, Granton J: Riociguat for the treatment of pulmonary hypertension. Expert Rev Respir Med. 2015;9(6):679-95. doi: 10.1586/17476348.2015.1106316. Epub 2015 Nov 24. [PubMed:26599488]
  3. Humbert M, Ghofrani HA: The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016 Jan;71(1):73-83. doi: 10.1136/thoraxjnl-2015-207170. Epub 2015 Jul 28. [PubMed:26219978]
  4. Conole D, Scott LJ: Riociguat: first global approval. Drugs. 2013 Nov;73(17):1967-75. doi: 10.1007/s40265-013-0149-5. [PubMed:24218053]
  5. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]
External Links
KEGG Drug
D09572
PubChem Compound
11304743
PubChem Substance
310264904
ChemSpider
9479719
ChEBI
76018
ChEMBL
CHEMBL2107834
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Riociguat
ATC Codes
C02KX05 — Riociguat
AHFS Codes
  • 48:48.00 — Vasodilating Agents
FDA label
Download (1.55 MB)
MSDS
Download (246 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableDrug Drug Interaction (DDI)1
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailablePharmacology, Clinical1
1CompletedOtherHIV-DDI1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentPharmacology, Clinical1
1CompletedTreatmentPulmonary Disease, Chronic Obstructive / Pulmonary Hypertension (PH)1
1CompletedTreatmentPulmonary Hypertension (PH)1
2Active Not RecruitingTreatmentDigital Ulcers / Scleroderma1
2Active Not RecruitingTreatmentPulmonary Hypertension (PH)1
2Active Not RecruitingTreatmentPulmonary Hypertension (PH) / Ventricular Dysfunction, Left1
2Active Not RecruitingTreatmentScleroderma, Systemic1
2CompletedNot AvailableRaynaud's Disease1
2CompletedTreatmentPulmonary Hypertension (PH)2
2Not Yet RecruitingTreatmentChronic Thromboembolic Disease (CTED) / Exercise Intolerance Post PEA Surgery1
2RecruitingTreatmentChronic Thromboembolic Pulmonary Hypertension1
2RecruitingTreatmentHeart Failure With Normal Ejection Fraction / Pulmonary Hypertension (PH)1
2RecruitingTreatmentSickle Cell Disorders1
2TerminatedTreatmentCystic Fibrosis (CF)1
2TerminatedTreatmentIdiopathic Interstitial Pneumonias / Hypertension,Pulmonary1
2TerminatedTreatmentPulmonary Hypertension (PH) / Ventricular Dysfunction, Left2
2WithdrawnTreatmentCoronary Artery Disease1
3Active Not RecruitingTreatmentPulmonary Hypertension (PH)2
3CompletedTreatmentPulmonary Hypertension (PH)3
3RecruitingTreatmentPulmonary Hypertension (PH)1
4CompletedNot AvailableAltitude Sickness / Pulmonary Hypertension (PH)1
4CompletedTreatmentPulmonary / Pulmonary Hypertension (PH)1
4RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
4RecruitingTreatmentPulmonary Hypertension (PH)1
4RecruitingTreatmentSarcoidosis1
Not AvailableCompletedNot AvailablePulmonary Hypertension (PH)2
Not AvailableNo Longer AvailableNot AvailablePulmonary Hypertension (PH)1
Not AvailableRecruitingNot AvailablePulmonary Hypertension (PH)2
Not AvailableRecruitingDiagnosticChronic Thromboembolic Pulmonary Hypertension / Sleep Disordered Breathing (SDB)1
Not AvailableRecruitingTreatmentChronic Thromboembolic Pulmonary Hypertension1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral0.5 mg
TabletOral1 mg
TabletOral1.5 mg
TabletOral2 mg
TabletOral2.5 mg
Tablet, film coatedOral.5 mg/1
Tablet, film coatedOral0.5 mg
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral1 mg
Tablet, film coatedOral1.5 mg
Tablet, film coatedOral1.5 mg/1
Tablet, film coatedOral2 mg/1
Tablet, film coatedOral2 mg
Tablet, film coatedOral2.5 mg
Tablet, film coatedOral2.5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7173037No2007-02-062023-04-25Us
US6743798No2004-06-012019-07-16Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility4 mg/L at 25°CFDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0682 mg/mLALOGPS
logP2.27ALOGPS
logP2.69ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)18.9ChemAxon
pKa (Strongest Basic)3.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area138.07 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity135.25 m3·mol-1ChemAxon
Polarizability41.9 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrazolopyridines. These are compounds containing a pyrazolopyridine skeleton, which consists of a pyrazole fused to a pyridine. Pyrazole is 5-membered ring consisting of three carbon atoms and two adjacent nitrogen centers. Pyridine is a 6-membered ring with four carbon and one nitrogen atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyrazolopyridines
Sub Class
Not Available
Direct Parent
Pyrazolopyridines
Alternative Parents
Aminopyrimidines and derivatives / Fluorobenzenes / Pyridines and derivatives / Aryl fluorides / Imidolactams / Pyrazoles / Carbamate esters / Heteroaromatic compounds / Organic carbonic acids and derivatives / Azacyclic compounds
show 6 more
Substituents
Pyrazolopyridine / Aminopyrimidine / Halobenzene / Fluorobenzene / Aryl fluoride / Aryl halide / Pyridine / Pyrimidine / Benzenoid / Imidolactam
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, carbamate ester, aminopyrimidine, pyrazolopyridine (CHEBI:76018)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
Stimulator
General Function
Heme binding
Specific Function
Has guanylyl cyclase on binding to the beta-1 subunit.Isoform 2 acts as a negative regulator of guanylyl cyclase activity as it forms non-functional heterodimers with the beta subunits.
Gene Name
GUCY1A2
Uniprot ID
P33402
Uniprot Name
Guanylate cyclase soluble subunit alpha-2
Molecular Weight
81749.185 Da
References
  1. Soeiro-Pereira PV, Falcai A, Kubo CA, Oliveira-Junior EB, Marques OC, Antunes E, Condino-Neto A: BAY 41-2272, a soluble guanylate cyclase agonist, activates human mononuclear phagocytes. Br J Pharmacol. 2012 Jul;166(5):1617-30. doi: 10.1111/j.1476-5381.2011.01764.x. [PubMed:22044316]
  2. Humbert M, Ghofrani HA: The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016 Jan;71(1):73-83. doi: 10.1136/thoraxjnl-2015-207170. Epub 2015 Jul 28. [PubMed:26219978]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
Molecular Weight
57610.165 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Khaybullina D, Patel A, Zerilli T: Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P T. 2014 Nov;39(11):749-58. [PubMed:25395817]

Drug created on November 13, 2013 16:07 / Updated on November 18, 2018 13:32