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Details

Stereochemistry ACHIRAL
Molecular Formula C20H19FN8O2
Molecular Weight 422.4164
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of RIOCIGUAT

SMILES

CN(c1c(=N)[nH]c(-c2c3cccnc3n(Cc4ccccc4F)n2)nc1N)C(=O)OC

InChI

InChIKey=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)

HIDE SMILES / InChI

Description
Curator's Comment:: http://www.fiercebiotech.com/biotech/bayer-s-riociguat-for-patients-chronic-thromboembolic-pulmonary-hypertension-and-pulmonary; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717417/

Riociguat is a potent, oral stimulator of soluble guanylate cyclase (sGC). It is the first member of a novel class of compounds, being developed by Bayer as an investigational, oral treatment to target a key molecular mechanism underlying pulmonary hypertension (PH). Riociguat demonstrated robust clinical efficacy in two separate PH indications: chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension(PAH). Riociguat works in two ways: it sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding and 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. Through this unique way of working, riociguat decreases blood pressure within the pulmonary arteries that take blood from the heart to the lungs, reducing pressure on the heart leading to improved patient outcomes.

CNS Activity

Curator's Comment:: Riociguat penetrated the blood/ brain barrier in rat to a low extent and no CNS activity was noted.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ADEMPAS

Approved Use

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; pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening.

Launch Date

1381190400000
Primary
ADEMPAS

Approved Use

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; pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening.

Launch Date

1381190400000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
29.7 μg/L
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RIOCIGUAT plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
158 μg × h/L
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RIOCIGUAT plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.67 h
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RIOCIGUAT plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
5%
RIOCIGUAT plasma
Homo sapiens
Doses

Doses

DosePopulationAdverse events​
2.5 mg single, oral
Highest studied dose
Dose: 2.5 mg
Route: oral
Route: single
Dose: 2.5 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Other AEs: Headache, Flushing...
Other AEs:
Headache (mild, 17%)
Flushing (mild, 17%)
Nasal congestion (mild, 4%)
Sources:
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Other AEs: Vomiting, Headache...
Other AEs:
Vomiting (mild, 4%)
Headache (moderate, 22%)
Glutamate dehydrogenase increased (4%)
Micturition urgency (mild, 9%)
Flushing (mild, 22%)
Hypotension (moderate, 4%)
Sources:
2.5 mg 3 times / day steady, oral
Highest studied dose
Dose: 2.5 mg, 3 times / day
Route: oral
Route: steady
Dose: 2.5 mg, 3 times / day
Sources:
unhealthy, 51.9 years
Health Status: unhealthy
Age Group: 51.9 years
Sex: M+F
Sources:
1 mg 3 times / day steady, oral
Recommended
Dose: 1 mg, 3 times / day
Route: oral
Route: steady
Dose: 1 mg, 3 times / day
Sources:
pregnant, adult
Health Status: pregnant
Age Group: adult
Sex: F
Sources:
Other AEs: Fetal damage...
AEs

AEs

AESignificanceDosePopulation
Flushing mild, 17%
2.5 mg single, oral
Highest studied dose
Dose: 2.5 mg
Route: oral
Route: single
Dose: 2.5 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Headache mild, 17%
2.5 mg single, oral
Highest studied dose
Dose: 2.5 mg
Route: oral
Route: single
Dose: 2.5 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Nasal congestion mild, 4%
2.5 mg single, oral
Highest studied dose
Dose: 2.5 mg
Route: oral
Route: single
Dose: 2.5 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Glutamate dehydrogenase increased 4%
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Flushing mild, 22%
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Vomiting mild, 4%
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Micturition urgency mild, 9%
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Headache moderate, 22%
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Hypotension moderate, 4%
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, 33-36 years
Health Status: healthy
Age Group: 33-36 years
Sex: M
Sources:
Fetal damage
1 mg 3 times / day steady, oral
Recommended
Dose: 1 mg, 3 times / day
Route: oral
Route: steady
Dose: 1 mg, 3 times / day
Sources:
pregnant, adult
Health Status: pregnant
Age Group: adult
Sex: F
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major [Km 1.1 uM]
yes (co-administration study)
Comment: ketoconzaole increased riociguat exposure by 2.5-fold
Page: 21, 28, 29
minor [Km 100 uM]
yes (co-administration study)
Comment: ketoconazole increases AUC to riociguat 2.5-fold, clarithromycin increases AUC of riociguat by 40%, bosentan decreases expsures by 27%
Page: 21, 28, 29, 30
minor [Km 11 uM]
yes (co-administration study)
Comment: ketoconzaole increased riociguat exposure by 2.5-fold
Page: 21, 28, 29
minor [Km 22 uM]
yes (co-administration study)
Comment: ketoconzaole increased riociguat exposure by 2.5-fold
Page: 21, 28, 29
yes
yes (co-administration study)
Comment: ketoconzaole increased riociguat exposure by 2.5-fold
Page: 28, 29
yes
yes (co-administration study)
Comment: ketoconzaole increased riociguat exposure by 2.5-fold
Page: 28, 29
PubMed

PubMed

TitleDatePubMed
Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy.
2009 Mar
Riociguat, an oral soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension.
2009 Sep
Animal models related to congenital heart disease and clinical research in pulmonary hypertension.
2010
Gateways to clinical trials.
2010 Mar
Patents

Sample Use Guides

The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of the drug, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day.
Route of Administration: Oral
Human fetal airway smooth muscle (fASM) cells were derived from 18-20 weeks PCA fetuses. Hyperoxia effects were inhibited in the presence of riociguat, a sGC stimulator (50mg/ml, 24 h each).
Name Type Language
RIOCIGUAT
DASH   INN   JAN   MI   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
RIOCIGUAT [WHO-DD]
Common Name English
BAY 63-2521
Code English
RIOCIGUAT [VANDF]
Common Name English
RIOCIGUAT [USAN]
Common Name English
RIOCIGUAT [EP MONOGRAPH]
Common Name English
RIOCIGUAT [MI]
Common Name English
RIOCIGUAT [JAN]
Common Name English
RIOCIGUAT [USP-RS]
Common Name English
ADEMPAS
Brand Name English
METHYL N-(4,6-DIAMINO-2-(1-((2-FLUOROPHENYL)METHYL)-1H-PYRAZOLO(3,4-B)PYRIDIN-3-YL)PYRIMIDIN-5-YL)-N-METHYLCARBAMATE
Systematic Name English
BAY-63-2521
Code English
RIOCIGUAT [ORANGE BOOK]
Common Name English
RIOCIGUAT [INN]
Common Name English
Classification Tree Code System Code
EMA ASSESSMENT REPORTS ADEMPAS (AUTHORIZED: HYPERTENSION, PULMONARY)
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
NDF-RT N0000190485
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
FDA ORPHAN DRUG 406913
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
FDA ORPHAN DRUG 669718
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
FDA ORPHAN DRUG 439514
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
FDA ORPHAN DRUG 392113
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
WHO-ATC C02KX05
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
EU-Orphan Drug EU/3/14/1299
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
NCI_THESAURUS C29707
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
Code System Code Type Description
EVMPD
SUB32880
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
NCI_THESAURUS
C152225
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
INN
8857
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
ChEMBL
CHEMBL2107834
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
USP_CATALOG
1604519
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY USP-RS
DRUG CENTRAL
4807
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
NDF-RT
N0000190484
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY Guanylate Cyclase Stimulators [MoA]
PUBCHEM
11304743
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
FDA UNII
RU3FE2Y4XI
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
JAPANESE REVIEW
ADEMPAS
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY APPROVED JANUARY 2014
CAS
625115-55-1
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
RXCUI
1439816
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY RxNorm
MERCK INDEX
M9628
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY Merck Index
IUPHAR
5257
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
DRUG BANK
DB08931
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY
WIKIPEDIA
RIOCIGUAT
Created by admin on Fri Jun 25 21:07:58 UTC 2021 , Edited by admin on Fri Jun 25 21:07:58 UTC 2021
PRIMARY