VORAPAXAR SULFATE

US Previously Marketed

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 Search

SMILES

OS(O)(=O)=O.CCOC(=O)N[C@@H]1CC[C@@H]2[C@H](C[C@@H]3[C@@H]([C@@H](C)OC3=O)[C@H]2\C=C\C4=CC=C(C=N4)C5=CC=CC(F)=C5)C1

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

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf
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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Proteinase-activated receptor 1 5 Target ID: P25116 Gene ID: 2149.0 Gene Symbol: F2R Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=23222541	Antagonist 2849		13.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Myocardial infarction 125 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf	Preventing		Approved 8583	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 2014
Peripheral arterial disease 22 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf	Preventing		Approved 8583	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 2014

C_max

Value	Dose	Co-administered	Analyte	Population
262 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27121783	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

Value	Dose	Co-administered	Analyte	Population
18400 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27121783	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
240 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27121783	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

Dose	Population	Adverse events
40 mg single, oral Highest studied dose Dose: 40 mg Route: oral Route: single Dose: 40 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19286091	unhealthy, 63.5 years Health Status: unhealthy Age Group: 63.5 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19286091	Sources: https://pubmed.ncbi.nlm.nih.gov/19286091
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000MedR.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000MedR.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000MedR.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf	Other AEs: Bleeding... Other AEs: Bleeding Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 1057 P-gp 1741 CYP2A6 879 CYP2C19 2057 CYP1A2 2153 CYP2B6 926 CYP2E1 1060 CYP3A4/5 296 OATP1B1 1079 OATP1B3 961 OAT1 725 OCT2 779 OAT3 747 BCRP 910 Ca2+ channels 59	CYP2J2 71 P-gp 2052

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=120 Page: 120.0	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=120 Page: 120.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=120 Page: 120.0	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
Ca2+ channels 62	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=62 Page: 62.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=63 Page: 63.0	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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=63 Page: 63.0
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=73 Page: 73.0	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] Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=73 Page: 73.0
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	yes [IC50 2.2 uM]
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=39 Page: 39.0	yes [IC50 2.5 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [IC50 30 uM]	no (co-administration study) Comment: Vorapaxar did not affect the pharmacokinetics or pharmacodynamics of warfarin. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=70 Page: 70.0

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=63 Page: 63.0	no
CYP2J2 71	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=100 Page: 100.0	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=100 Page: 100.0	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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ClinPharmR.pdf#page=100 Page: 100.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf#page=37 Page: 37.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:82702	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82702
ChemicalBook	CB32628522	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32628522
MolPort	MolPort-039-062-225	https://www.molport.com/shop/molecule-link/MolPort-039-062-225
Selleck Chemicals	vorapaxar	http://www.selleckchem.com/products/vorapaxar.html
ZINC	ZINC000003925861	http://zinc15.docking.org/substances/ZINC000003925861

PubMed

Title	Date	PubMed
		252160423
Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding cangrelor.	2015 Apr 15	25728646
Vorapaxar in atherosclerotic disease management.	2015 May	25680760

Patents

Sample Use Guides

In Vivo Use Guide

One tablet of ZONTIVITY orally once daily (Tablets: 2.08 mg vorapaxar)

Route of Administration: Oral

In Vitro Use Guide

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.

Name

Type

Language

ZONTIVITY

Preferred Name

English

VORAPAXAR SULFATE

Official Name

English

VORAPAXAR SULFATE [MI]

Common Name

English

VORAPAXAR SULFATE [ORANGE BOOK]

Common 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