Vorapaxar

Identification

Summary

Vorapaxar is a platelet aggregation inhibitor used to reduce thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD).

Brand Names
Zontivity
Generic Name
Vorapaxar
DrugBank Accession Number
DB09030
Background

Vorapaxar is a tricyclic himbacine-derived selective inhibitor of protease activated receptor (PAR-1) indicated for reducing the incidence of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). By inhibiting PAR-1, a thrombin receptor expressed on platelets, vorapaxar prevents thrombin-related platelet aggregation.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 492.5817
Monoisotopic: 492.242435759
Chemical Formula
C29H33FN2O4
Synonyms
  • [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(E)-2-[5-(3-Fluorophényl)-2-pyridinyl]vinyl}-1-méthyl-3-oxododécahydronaphto[2,3-c]furan-6-yl]carbamate d'éthyle
  • 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
  • Carbamic acid, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-, ethyl ester
  • Ethyl N-[(3R,3aS,4S,4aR,7R,8aR,9aR)-4-[(E)-2-[5-(3-fluorophenyl)-2-pyridyl]vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f]isobenzofuran-7-yl]carbamate
  • Vorapaxar
External IDs
  • MFCD16038876
  • ZCE93644N2

Pharmacology

Indication

Vorapaxar is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). It is usually co-administered with acetylsalicylic acid (ASA) and/or clopidogrel, and should therefore be administered as an addition to these medications as it has not been studied alone.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

Vorapaxar inhibits platelet aggregation through the reversible antagonism of protease-activated receptor 1 (PAR-1), also known as thrombin receptor. PARs are a family of G-protein coupled receptors highly expressed on platelets and activated by serine protease activity of thrombin to mediate thrombotic response. By blocking PAR-1 activating, vorapaxar inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen or a thromboxane mimetic.

TargetActionsOrganism
AProteinase-activated receptor 1
antagonist
Humans
Absorption

After oral administration, vorapaxar is rapidly absorbed and peak concentrations occur at a median tmax of 1 hour under faster conditions. Vorapaxar may be taken with or without food as ingestion with a high-fat meal did not result in meaningful changes in AUC. The mean absolute bioavailability is 100%.

Volume of distribution

424 L

Protein binding

Vorapaxar is extensively bound (>99%) to human plasma proteins, such as human serum albumin.

Metabolism

Vorapaxar is metabolized to its major circulating metabolite, M20, and its predominant metabolite excreted into feces, M19, by CYP3A4 and CYP 2J2.

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Route of elimination

Vorapaxar is primarily eliminated as its metabolite M19 through the feces (91.5%), and partially eliminated in the urine (8.5%).

Half-life

Vorapaxar has an effective half life of 3-4 days and an apparent terminal half life of 8 days.

Clearance

Not Available

Adverse Effects
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Toxicity

There is an increased risk of bleeding and intracranial hemorrhage (ICH), which is why the use of vorapaxar is contraindicated in patients with a history of stroke, trans-ischemic attack (TIA), ICH, or active pathological bleeding such as peptic ulcer. Animal studies have suggested that there is a low probability of embryo/fetal toxicities, however there are no adequate and well-controlled studies describing use in pregnant women. Vorapaxar should also be avoided during breastfeeding as it is unknown whether vorapaxar or its metabolites are excreted in human milk, however it has been shown to be actively secreted in the milk of rats.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Vorapaxar can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Vorapaxar can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Abciximab.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Vorapaxar.
AbirateroneThe metabolism of Vorapaxar can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Vorapaxar can be decreased when combined with Acalabrutinib.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Vorapaxar.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Acemetacin is combined with Vorapaxar.
AcenocoumarolThe risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Acenocoumarol.
AcetaminophenThe metabolism of Vorapaxar can be increased when combined with Acetaminophen.
Interactions
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Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Additive antiplatelet activity may increase the risk of bleeding. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of vorapaxar and may reduce its serum concentration.
  • Exercise caution with grapefruit products. Coadministration of vorapaxar with moderate CYP3A4 inhibitors does not require intervention, but coadministration with strong inhibitors should be avoided.
  • Take with or without food.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Vorapaxar sulfateIN66038E6C705260-08-8NQRYCIGCIAWEIC-CKLVGUEFSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZontivityTablet, film coated2.08 mg/1OralAralez Pharmaceuticals Us Inc.2014-05-08Not applicableUS flag
ZontivityTablet2.5 mgOralToprol Acquisition, LlcNot applicableNot applicableCanada flag
ZontivityTablet, film coated2.08 mg/1OralMerck Sharp & Dohme Corp.2014-05-082016-09-13US flag

Categories

ATC Codes
B01AC26 — Vorapaxar
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as naphthofurans. These are compounds containing a furan ring fused to a naphthalene moiety. Furan is a 5 membered- ring aromatic ring with four carbon and one oxygen atoms. Naphthalene is a polycyclic aromatic hydrocarbon made up of two fused benzene rings.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Naphthofurans
Sub Class
Not Available
Direct Parent
Naphthofurans
Alternative Parents
Phenylpyridines / Fluorobenzenes / Aryl fluorides / Gamma butyrolactones / Tetrahydrofurans / Carbamate esters / Heteroaromatic compounds / Carboxylic acid esters / Organic carbonic acids and derivatives / Oxacyclic compounds
show 8 more
Substituents
3-phenylpyridine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxylic acid derivative
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, carbamate ester, pyridines, lactone, naphthofuran (CHEBI:82702)
Affected organisms
Not Available

Chemical Identifiers

UNII
ZCE93644N2
CAS number
618385-01-6
InChI Key
ZBGXUVOIWDMMJE-QHNZEKIYSA-N
InChI
InChI=1S/C29H33FN2O4/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/h4-9,12-13,16-17,20,23-27H,3,10-11,14-15H2,1-2H3,(H,32,34)/b12-9+/t17-,20+,23-,24-,25+,26-,27+/m1/s1
IUPAC Name
ethyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-dodecahydronaphtho[2,3-c]furan-6-yl]carbamate
SMILES
[H][C@@]12C[C@]3([H])C[C@@H](CC[C@@]3([H])[C@H](\C=C\C3=CC=C(C=N3)C3=CC(F)=CC=C3)[C@]1([H])[C@@H](C)OC2=O)NC(=O)OCC

References

General References
  1. Ghosal A, Lu X, Penner N, Gao L, Ramanathan R, Chowdhury SK, Kishnani NS, Alton KB: Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab Dispos. 2011 Jan;39(1):30-8. doi: 10.1124/dmd.110.035493. Epub 2010 Oct 6. [Article]
  2. Lhermusier T, Baker NC, Waksman R: Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding cangrelor. Am J Cardiol. 2015 Apr 15;115(8):1154-61. doi: 10.1016/j.amjcard.2015.01.551. Epub 2015 Feb 3. [Article]
  3. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD, Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G, Nicolau JC, Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, Whellan DJ, Widimsky P, Strony J, Harrington RA, Mahaffey KW: Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012 Jan 5;366(1):20-33. doi: 10.1056/NEJMoa1109719. Epub 2011 Nov 13. [Article]
  4. Cheng JW, Colucci V, Howard PA, Nappi JM, Spinler SA: Vorapaxar in atherosclerotic disease management. Ann Pharmacother. 2015 May;49(5):599-606. doi: 10.1177/1060028015571410. Epub 2015 Feb 13. [Article]
KEGG Drug
D09765
PubChem Compound
10077130
PubChem Substance
310264983
ChemSpider
8252668
BindingDB
50261110
RxNav
1537034
ChEBI
82702
ChEMBL
CHEMBL493982
ZINC
ZINC000003925861
PDBe Ligand
VPX
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Vorapaxar
PDB Entries
3vw7
FDA label
Download (651 KB)
MSDS
Download (49.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedHealth Services ResearchCoronary Artery Disease (CAD) / Myocardial Infarction / Peripheral Vascular Disease Patient1
4CompletedTreatmentDiabetes Mellitus / Myocardial Infarction / Peripheral Arterial Disease (PAD)1
4CompletedTreatmentHealthy Volunteers1
4CompletedTreatmentMyocardial Infarction1
4Not Yet RecruitingHealth Services ResearchCoronary Artery Disease (CAD)1
4Unknown StatusTreatmentPeripheral Arterial Disease (PAD)1
4WithdrawnOtherPeripheral Artery Disease (PAD)1
3CompletedPreventionAtherosclerosis / Cerebrovascular Accident / Ischaemia / Myocardial Infarction1
3CompletedPreventionAtherosclerosis / Cerebrovascular Accident / Ischaemia / Myocardial Infarction / Peripheral Arterial Disease (PAD)1
3TerminatedPreventionAtherosclerosis / Myocardial Infarction / Myocardial Ischemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral2.5 mg
Tablet, film coatedOral
Tablet, film coatedOral2.08 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7304078No2007-12-042024-04-06US flag
US7235567No2007-06-262021-06-13US flag
US7713999No2010-05-112024-05-30US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP5.39ChEMBL
Predicted Properties
PropertyValueSource
Water Solubility0.000654 mg/mLALOGPS
logP4.9ALOGPS
logP5.04ChemAxon
logS-5.9ALOGPS
pKa (Strongest Acidic)14.78ChemAxon
pKa (Strongest Basic)4.32ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77.52 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity134.52 m3·mol-1ChemAxon
Polarizability53.85 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Thrombin receptor activity
Specific Function
High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation and in vascular development.
Gene Name
F2R
Uniprot ID
P25116
Uniprot Name
Proteinase-activated receptor 1
Molecular Weight
47439.83 Da
References
  1. Bonaca MP, Morrow DA: SCH 530348: a novel oral thrombin receptor antagonist. Future Cardiol. 2009 Sep;5(5):435-42. doi: 10.2217/fca.09.27. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Nair AS: Vorapaxar: The missing link in antiplatelet therapy! J Anaesthesiol Clin Pharmacol. 2017 Apr-Jun;33(2):269-270. doi: 10.4103/joacp.JOACP_363_16. [Article]
  2. Gryka RJ, Buckley LF, Anderson SM: Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease. Drugs R D. 2017 Mar;17(1):65-72. doi: 10.1007/s40268-016-0158-4. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
Molecular Weight
57610.165 Da
References
  1. Nair AS: Vorapaxar: The missing link in antiplatelet therapy! J Anaesthesiol Clin Pharmacol. 2017 Apr-Jun;33(2):269-270. doi: 10.4103/joacp.JOACP_363_16. [Article]
  2. Gryka RJ, Buckley LF, Anderson SM: Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease. Drugs R D. 2017 Mar;17(1):65-72. doi: 10.1007/s40268-016-0158-4. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on February 09, 2015 22:24 / Updated on August 04, 2021 18:23