RIOCIGUAT

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H19FN8O2
Molecular Weight	422.4157
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC(=O)N(C)C1=C(N)N=C(N=C1N)C2=NN(CC3=C(F)C=CC=C3)C4=C2C=CC=N4

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
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204819s002lbl.pdf
Curator's Comment: description was created based on several sources, including 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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Soluble guanylate cyclase 34 Target ID: CHEMBL2111348 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204819s002lbl.pdf	Agonist 2678

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic thromboembolic pulmonary hypertension 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204819s002lbl.pdf	Primary		Approved 8429	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 2013
Pulmonary arterial hypertension 35 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204819s002lbl.pdf	Primary		Approved 8429	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 2013

C_max

Value	Dose	Co-administered	Analyte	Population
29.7 μg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26507720	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

Value	Dose	Co-administered	Analyte	Population
158 μg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26507720	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.67 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26507720	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204819s006lbl.pdf			RIOCIGUAT plasma	Homo sapiens

Doses

Dose	Population	Adverse events
2.5 mg single, oral Highest studied dose Dose: 2.5 mg Route: oral Route: single Dose: 2.5 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 24 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	Other AEs: Headache, Flushing... Other AEs: Headache (mild, 17%) Flushing (mild, 17%) Nasal congestion (mild, 4%) Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	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: https://pubmed.ncbi.nlm.nih.gov/27096084
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: https://pubmed.ncbi.nlm.nih.gov/32299845	unhealthy, 51.9 years n = 60 Health Status: unhealthy Condition: early diffuse cutaneous systemic sclerosis Age Group: 51.9 years Sex: M+F Population Size: 60 Sources: https://pubmed.ncbi.nlm.nih.gov/32299845	Sources: https://pubmed.ncbi.nlm.nih.gov/32299845
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204819s000lbl.pdf	pregnant, adult Health Status: pregnant Age Group: adult Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204819s000lbl.pdf	Other AEs: Fetal damage... Other AEs: Fetal damage Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204819s000lbl.pdf

AEs

AE	Significance	Dose	Population
Flushing	mild, 17%	2.5 mg single, oral Highest studied dose Dose: 2.5 mg Route: oral Route: single Dose: 2.5 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 24 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Headache	mild, 17%	2.5 mg single, oral Highest studied dose Dose: 2.5 mg Route: oral Route: single Dose: 2.5 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 24 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
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: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 24 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Glutamate dehydrogenase increased	4%	1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Flushing	mild, 22%	1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Vomiting	mild, 4%	1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Micturition urgency	mild, 9%	1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Headache	moderate, 22%	1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
Hypotension	moderate, 4%	1 mg single, intravenous Dose: 1 mg Route: intravenous Route: single Dose: 1 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27096084	healthy, 33-36 years n = 22 Health Status: healthy Age Group: 33-36 years Sex: M Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27096084
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204819s000lbl.pdf	pregnant, adult Health Status: pregnant Age Group: adult Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204819s000lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A1 110 CYP2C19 1478 P-gp 1461 BCRP 699	CYP1A1 349 CYP3A4/5 85 CYP2C8 693 CYP2J2 56 P-gp 1537 BCRP 561	CYP3A 129 CYP1A2 701 CYP2B6 547 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	no [IC50 >50 uM]
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	no [IC50 >50 uM]
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	no [IC50 >50 uM]
CYP3A 298	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	no [IC50 >50 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	no
CYP1A1 218	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	strong [IC50 0.8 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28.0	yes [IC50 44 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A1 349	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29	major [Km 1.1 uM]	yes (co-administration study) Comment: ketoconzaole increased riociguat exposure by 2.5-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29
CYP3A4/5 85	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29, 30	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% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29, 30
CYP2J2 56	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29	minor [Km 11 uM]	yes (co-administration study) Comment: ketoconzaole increased riociguat exposure by 2.5-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29	minor [Km 22 uM]	yes (co-administration study) Comment: ketoconzaole increased riociguat exposure by 2.5-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 21, 28, 29
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28, 29	yes	yes (co-administration study) Comment: ketoconzaole increased riociguat exposure by 2.5-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28, 29
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28, 29	yes	yes (co-administration study) Comment: ketoconzaole increased riociguat exposure by 2.5-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf Page: 28, 29

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:76018	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:76018
ChemicalBook	CB62473752	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62473752
MolPort	MolPort-023-219-120	https://www.molport.com/shop/molecule-link/MolPort-023-219-120
ZINC	ZINC000003819392	http://zinc15.docking.org/substances/ZINC000003819392

PubMed

Title	Date	PubMed
NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle.	2002 Jul	12086987
Pulmonary arterial hypertension: on the way to a manageable disease.	2008 Sep	18729002
Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy.	2009 Mar	20956121
Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.	2009 May	19263460
Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models.	2010 Aug	20613628
Riociguat: an upcoming therapy in chronic thromboembolic pulmonary hypertension?	2010 Mar	20956169
Riociguat for pulmonary hypertension.	2010 Mar	20230258
[Pulmonary arterial hypertension--a rare form of pulmonary hypertension].	2010 May	20509110
Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.	2010 Oct	20530034

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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

Official 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 [WHO-DD]

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 [USP MONOGRAPH]

Common Name

English

RIOCIGUAT [ORANGE BOOK]

Common Name

English

riociguat [INN]

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

ADEMPAS (AUTHORIZED: HYPERTENSION, PULMONARY)