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Riociguat

PubChem CID
11304743
Structure
Riociguat_small.png
Riociguat_3D_Structure.png
Riociguat__Crystal_Structure.png
Molecular Formula
Synonyms
  • Riociguat
  • 625115-55-1
  • Adempas
  • BAY 63-2521
  • Riociguat (BAY 63-2521)
Molecular Weight
422.4 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2006-10-26
  • Modify:
    2025-01-11
Description
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.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Riociguat.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 2
View All
COD Number
Associated Article
Zhou, Xinbo; Hu, Xiurong; Gu, Jianming; Zhu, Jianrong. Comparison of the crystal structures and thermochemistry of a novel soluble guanylate cyclase stimulator riociguat and its solvates.. Acta crystallographica Section B, Structural science, crystal engineering and materials 2017;73(Pt 5):891-898. DOI: 10.1107/S2052520617006011
Crystal Structure Depiction
Crystal Structure Depiction
Hermann-Mauguin space group symbol
P -1
Hall space group symbol
-P 1
Space group number
2
a
8.0917 Å
b
10.8937 Å
c
11.7949 Å
α
88.3380 °
β
82.344 °
γ
78.787 °
Z
2
Z'
1
Residual factor
0.0818

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

methyl N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-N-methylcarbamate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 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)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

WXXSNCNJFUAIDG-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CN(C1=C(N=C(N=C1N)C2=NN(C3=C2C=CC=N3)CC4=CC=CC=C4F)N)C(=O)OC
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C20H19FN8O2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 PharmGKB ID

2.3.14 Pharos Ligand ID

2.3.15 RXCUI

2.3.16 Wikidata

2.3.17 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Adempas
  • BAY 63-2521
  • BAY-63-2521
  • riociguat

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
422.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
1.6
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
9
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
422.16150004 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
422.16150004 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
138 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
31
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
618
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Solubility

4 mg/L at 25°C
FDA label

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Cardiovascular system -> Antihypertensives
S92 | FLUOROPHARMA | List of ~340 ATC classified fluoro-pharmaceuticals | DOI:10.5281/zenodo.5979646
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Enzyme Activators
Human drug -> Prescription; None (Tentative Approval); Active ingredient (RIOCIGUAT)
Human drug -> Prescription
Human drugs -> Antihypertensives for pulmonary arterial hypertension -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug

5 Chemical Vendors

6 Drug and Medication Information

6.1 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%).
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.  

6.2 LiverTox Summary

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.

6.3 Drug Classes

Breast Feeding; Lactation; Enzyme Activators
Pulmonary Arterial Hypertension Agents

6.4 FDA Medication Guides

Drug
Active Ingredient
RIOCIGUAT
Form;Route
TABLET;ORAL
Company
BAYER HLTHCARE
Date
9/10/21

6.5 FDA Approved Drugs

6.6 FDA Orange Book

6.7 FDA National Drug Code Directory

6.8 Drug Labels

Drug and label
Active ingredient and drug

6.9 Clinical Trials

6.9.1 ClinicalTrials.gov

6.9.2 EU Clinical Trials Register

6.9.3 NIPH Clinical Trials Search of Japan

6.10 EMA Drug Information

1 of 2
Medicine
Category
Human drugs
Therapeutic area
Hypertension, Pulmonary
Active Substance
riociguat
INN/Common name
riociguat
Pharmacotherapeutic Classes
Antihypertensives for pulmonary arterial hypertension
Status
This medicine is authorized for use in the European Union
Company
Bayer AG
Market Date
2014-03-27
2 of 2
Type
Paediatric investigation
Active Substance
Therapeutic Area
Cardiovascular diseases
Drug Form
Film-coated tablet, Oral liquid
Administration Route
Oral use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2016-11-04

6.11 Japan PMDA Drugs

Brand Name
Adempas
Non-proprietary Name
Riociguat
Approval Date
January 2014
Review Document

7 Pharmacology and Biochemistry

7.1 MeSH Pharmacological Classification

Enzyme Activators
Compounds or factors that act on a specific enzyme to increase its activity. (See all compounds classified as Enzyme Activators.)

7.2 FDA Pharmacological Classification

1 of 2
FDA UNII
RU3FE2Y4XI
Active Moiety
RIOCIGUAT
Pharmacological Classes
Mechanisms of Action [MoA] - Guanylate Cyclase Stimulators
Pharmacological Classes
Established Pharmacologic Class [EPC] - Soluble Guanylate Cyclase Stimulator
FDA Pharmacology Summary
Riociguat is a Soluble Guanylate Cyclase Stimulator. The mechanism of action of riociguat is as a Guanylate Cyclase Stimulator.
2 of 2
Non-Proprietary Name
RIOCIGUAT
Pharmacological Classes
Soluble Guanylate Cyclase Stimulator [EPC]; Guanylate Cyclase Stimulators [MoA]

7.3 ATC Code

C02KX05

C - Cardiovascular system

C02 - Antihypertensives

C02K - Other antihypertensives

C02KX - Antihypertensives for pulmonary arterial hypertension

C02KX05 - Riociguat

7.4 Absorption, Distribution and Excretion

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.
Route of Elimination
Riociguat is eliminated in the urine (40%) and feces (53%), largely as metabolites.
Volume of Distribution
Volume of distribution at steady state = 30 L

7.5 Metabolism / Metabolites

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

7.6 Biological Half-Life

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

7.7 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.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human drugs -> Antihypertensives for pulmonary arterial hypertension -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements
H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P317, P330, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 25 reports by companies from 1 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

9.1.2 Hazard Classes and Categories

Acute Tox. 4 (100%)

10 Toxicity

10.1 Toxicological Information

10.1.1 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).

10.1.2 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.

10.1.3 Protein Binding

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

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Springer Nature References

12.4 Thieme References

12.5 Chemical Co-Occurrences in Literature

12.6 Chemical-Gene Co-Occurrences in Literature

12.7 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 FDA Orange Book Patents

13.4 Chemical Co-Occurrences in Patents

13.5 Chemical-Disease Co-Occurrences in Patents

13.6 Chemical-Gene Co-Occurrences in Patents

14 Interactions and Pathways

14.1 Protein Bound 3D Structures

14.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

14.2 Chemical-Target Interactions

14.3 Drug-Drug Interactions

14.4 Drug-Food Interactions

  • Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of riociguat and may reduce its serum concentration.
  • Take separate from antacids. Take at least 1 hour before or after antacids. Aluminum or magnesium hydroxide antacids may reduce riociguat absorption.
  • Take with or without food.

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 ChEBI Ontology

16.4 KEGG: Drug

16.5 KEGG: USP

16.6 KEGG: ATC

16.7 KEGG: Target-based Classification of Drugs

16.8 KEGG: Drug Groups

16.9 WHO ATC Classification System

16.10 FDA Pharm Classes

16.11 ChemIDplus

16.12 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

16.13 ChEMBL Target Tree

16.14 UN GHS Classification

16.15 NORMAN Suspect List Exchange Classification

16.16 EPA DSSTox Classification

16.17 FDA Drug Type and Pharmacologic Classification

16.18 PFAS and Fluorinated Organic Compounds in PubChem

16.19 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
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    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
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    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
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    https://echa.europa.eu/web/guest/legal-notice
    methyl[4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]methyl carbamate
    https://echa.europa.eu/substance-information/-/substanceinfo/100.169.606
    methyl[4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]methyl carbamate (EC: 641-755-1)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/174494
  6. FDA Global Substance Registration System (GSRS)
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  13. Comparative Toxicogenomics Database (CTD)
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  14. Drug Gene Interaction database (DGIdb)
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    http://www.dgidb.org/downloads
  15. IUPHAR/BPS Guide to PHARMACOLOGY
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    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  16. Therapeutic Target Database (TTD)
  17. Crystallography Open Database (COD)
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  18. DailyMed
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  28. Japan Chemical Substance Dictionary (Nikkaji)
  29. Japan Pharmaceuticals and Medical Devices Agency (PMDA)
  30. KEGG
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    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
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  31. Metabolomics Workbench
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  33. NIPH Clinical Trials Search of Japan
  34. NLM RxNorm Terminology
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  35. NORMAN Suspect List Exchange
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    https://creativecommons.org/licenses/by/4.0/
    Riociguat
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  36. PharmGKB
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  37. Pharos
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  38. Protein Data Bank in Europe (PDBe)
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    https://www.rcsb.org/pages/policies
  40. Springer Nature
  41. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  42. Wikidata
  43. Wikipedia
  44. PubChem
  45. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
  46. GHS Classification (UNECE)
  47. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  48. PATENTSCOPE (WIPO)
  49. NCBI
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