U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C29H33FN2O4.H2O4S
Molecular Weight 590.66
Optical Activity UNSPECIFIED
Defined Stereocenters 7 / 7
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of VORAPAXAR SULFATE

SMILES

OS(O)(=O)=O.[H][C@@]12C[C@]3([H])C[C@@H](CC[C@@]3([H])[C@]([H])(\C=C\C4=CC=C(C=N4)C5=CC(F)=CC=C5)[C@]1([H])[C@@H](C)OC2=O)NC(=O)OCC

InChI

InChIKey=NQRYCIGCIAWEIC-CKLVGUEFSA-N
InChI=1S/C29H33FN2O4.H2O4S/c1-3-35-29(34)32-23-10-11-24-20(14-23)15-26-27(17(2)36-28(26)33)25(24)12-9-22-8-7-19(16-31-22)18-5-4-6-21(30)13-18;1-5(2,3)4/h4-9,12-13,16-17,20,23-27H,3,10-11,14-15H2,1-2H3,(H,32,34);(H2,1,2,3,4)/b12-9+;/t17-,20+,23-,24-,25+,26-,27+;/m1./s1

HIDE SMILES / InChI

Molecular Formula C29H33FN2O4
Molecular Weight 492.5817
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 7 / 7
E/Z Centers 1
Optical Activity UNSPECIFIED

Molecular Formula H2O4S
Molecular Weight 98.078
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/26022529

Vorapaxar is a tricyclic himbacine-derived oral thrombin receptor antagonist that acts by reversible inhibition of the protease-activated receptor-1 (PAR-1). PAR-1 is expressed on platelets and its inhibition prevents platelets from aggregation. Vorapaxar is approved by FDA and is indicated for the reduction of recurring thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Vorapaxar at the same time may cause bleeding complications including intracranial haemorrhage (ICH), when compared to standard therapy alone. That is why Vorapaxar is contraindicated in patients with prior stroke, transient ischemic attack and ICH.

Originator

Curator's Comment: The drug was discovered by Schering-Plough and developed by Merck.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P25116
Gene ID: 2149.0
Gene Symbol: F2R
Target Organism: Homo sapiens (Human)
13.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Preventing
ZONTIVITY

Approved Use

Indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD).

Launch Date

1.39950726E12
Preventing
ZONTIVITY

Approved Use

Indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD).

Launch Date

1.39950726E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
262 ng/mL
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
VORAPAXAR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
18400 ng × h/mL
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
VORAPAXAR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
240 h
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
VORAPAXAR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
40 mg single, oral (starting)
Highest studied dose
Dose: 40 mg
Route: oral
Route: single
Dose: 40 mg
Sources:
unhealthy, 63.5 years
n = 173
Health Status: unhealthy
Condition: coronary artery disease
Age Group: 63.5 years
Sex: M+F
Population Size: 173
Sources:
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Disc. AE: Melaena, Rectal haemorrhage...
Other AEs: Venous thrombosis...
AEs leading to
discontinuation/dose reduction:
Melaena (0.2%)
Rectal haemorrhage (0.2%)
Haemorrhage intracranial (0.3%)
Haematuria (0.2%)
Epistaxis (0.4%)
Increased tendency to bruise (0.2%)
Anaemia (0.3%)
Visual acuity reduced (0.1%)
Hypertransaminasaemia (0.1%)
Transaminases abnormal (0.1%)
Initial insomnia (0.1%)
Depressive symptom (0.1%)
Varicose vein (0.1%)
Vein pain (0.1%)
Other AEs:
Venous thrombosis (0.1%)
Sources: Page: p. 142
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: intracranial hemorrhage | transient ischemic attack
Age Group: adult
Sources:
Other AEs: Bleeding...
AEs

AEs

AESignificanceDosePopulation
Venous thrombosis 0.1%
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Depressive symptom 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Hypertransaminasaemia 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Initial insomnia 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Transaminases abnormal 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Varicose vein 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Vein pain 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Visual acuity reduced 0.1%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Haematuria 0.2%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Increased tendency to bruise 0.2%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Melaena 0.2%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Rectal haemorrhage 0.2%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Anaemia 0.3%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Haemorrhage intracranial 0.3%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Epistaxis 0.4%
Disc. AE
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources: Page: p. 142
unhealthy, adult
n = 13186
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 13186
Sources: Page: p. 142
Bleeding
2.5 mg 1 times / day multiple, oral
Recommended
Dose: 2.5 mg, 1 times / day
Route: oral
Route: multiple
Dose: 2.5 mg, 1 times / day
Sources:
unhealthy, adult
Health Status: unhealthy
Condition: intracranial hemorrhage | transient ischemic attack
Age Group: adult
Sources:
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
yes [IC50 1.2 uM]
no (co-administration study)
Comment: Based on in vitro results, the DDI potential of vorapaxar (as a P-gp inhibitor) with digoxin (as a P-gp substrate), is not expected to be of clinical consequences 2.5 mg dose.
Page: 63.0
yes [IC50 1.5 uM]
no (co-administration study)
Comment: In vivo drug interaction studies with warfarin and rosiglitazone were performed as vorapaxar showed a very modest potential to inhibit CYP2C8 [IC50=1.5 µM]
Page: 73.0
yes [IC50 2.2 uM]
yes [IC50 2.5 uM]
yes [IC50 30 uM]
no (co-administration study)
Comment: Vorapaxar did not affect the pharmacokinetics or pharmacodynamics of warfarin.
Page: 70.0
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
yes
yes
yes (co-administration study)
Comment: Upon repeat co-administration, ketoconazole, a strong CYP3A inhibitor, increases the systemic exposures to vorapaxar by 2-fold, while rifampin, a strong CYP3A inducer, decreases the systemic exposure to vorapaxar by 55%.
Page: 100.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity.
2008 Jun 12
Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist.
2011 Jan
Thrombin-receptor antagonist vorapaxar in acute coronary syndromes.
2012 Jan 5
Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding cangrelor.
2015 Apr 15
Vorapaxar in atherosclerotic disease management.
2015 May
Patents

Sample Use Guides

One tablet of ZONTIVITY orally once daily (Tablets: 2.08 mg vorapaxar)
Route of Administration: Oral
In human platelet-rich plasma,vorapaxar inhibited thrombin and TRAP-induced platelet aggregation with an IC50 of 47 and 25nM, respectively, without affecting aggregation induced by other reagents, such as ADP, TXA2 mimetic U46619 or collagen.
Substance Class Chemical
Created
by admin
on Fri Dec 15 23:59:59 UTC 2023
Edited
by admin
on Fri Dec 15 23:59:59 UTC 2023
Record UNII
IN66038E6C
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
VORAPAXAR SULFATE
MI   USAN   VANDF   WHO-DD  
USAN  
Official Name English
VORAPAXAR SULFATE [MI]
Common Name English
VORAPAXAR SULFATE [ORANGE BOOK]
Common Name English
ZONTIVITY
Brand Name English
Ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate sulfate
Common Name English
SCH 530348
Code English
VORAPAXAR SULFATE [USAN]
Common Name English
CARBAMIC ACID, ((1R,3AR,4AR,6R,8AR,9S,9AS)-9-((1E)-2-(5-(3-FLUOROPHENYL)-2-PYRIDINYL)ETHENYL)DODECAHYDRO-1-METHYL-3-OXONAPHTHO(2,3-C)FURAN-6-YL)-, ETHYL ESTER, SULFATE
Common Name English
VORAPAXAR SULFATE [VANDF]
Common Name English
SCH-530348
Code English
Vorapaxar sulfate [WHO-DD]
Common Name English
CARBAMIC ACID, N-((1R,3AR,4AR,6R,8AR,9S,9AS)-9-((1E)-2-(5-(3-FLUOROPHENYL)-2-PYRIDINYL)ETHENYL)DODECAHYDRO-1-METHYL-3-OXONAPHTHO(2,3-C)FURAN-6-YL)-, ETHYL ESTER, SULFATE (1:1)
Common Name English
VORAPAXAR SULFATE [JAN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C78274
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
EMA ASSESSMENT REPORTS ZONTIVITY (AUTHORIZED: MYOCARDIAL INFARCTION)
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
NCI_THESAURUS C1327
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
Code System Code Type Description
ChEMBL
CHEMBL493982
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
CAS
705260-08-8
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
MERCK INDEX
m11500
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY Merck Index
DRUG BANK
DBSALT001104
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
CHEBI
83314
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
EPA CompTox
DTXSID60990731
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
PUBCHEM
10077129
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
USAN
RR-17
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
EVMPD
SUB169817
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
DAILYMED
IN66038E6C
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
NCI_THESAURUS
C152913
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
SMS_ID
100000159561
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
FDA UNII
IN66038E6C
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY
RXCUI
1537050
Created by admin on Fri Dec 15 23:59:59 UTC 2023 , Edited by admin on Fri Dec 15 23:59:59 UTC 2023
PRIMARY RxNorm
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