Identification

Name
Vorapaxar
Accession Number
DB09030  (DB05692)
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
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
External IDs
MFCD16038876 / SCH 530348 / SCH-530348 / SCH530348 / ZCE93644N2
Product Ingredients
IngredientUNIICASInChI Key
Vorapaxar SulfateIN66038E6C705260-08-8NQRYCIGCIAWEIC-CKLVGUEFSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZontivityTablet2.5 mgOralAralez Pharmaceuticals Trading DacNot applicableNot applicableCanada
ZontivityTablet, film coated2.08 mg/1OralAralez Pharmaceuticals Us Inc.2014-05-08Not applicableUs
ZontivityTablet, film coated2.08 mg/1OralMerck Sharp & Dohme Limited2014-05-08Not applicableUs
Categories
UNII
ZCE93644N2
CAS number
618385-01-6
Weight
Average: 492.5817
Monoisotopic: 492.242435759
Chemical Formula
C29H33FN2O4
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
N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-dodecahydronaphtho[2,3-c]furan-6-yl]ethoxycarboximidic acid
SMILES
[H]\C(=C(\[H])[C@]1([H])[C@]2([H])[C@@]([H])(C)OC(=O)[C@]2([H])C[C@]2([H])C[C@@]([H])(CC[C@@]12[H])N=C(O)OCC)C1=NC=C(C=C1)C1=CC(F)=CC=C1

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.

Associated Conditions
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
Human
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.

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
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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Abciximab.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Vorapaxar.
AcenocoumarolThe risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Acenocoumarol.
Acetylsalicylic acidThe risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Acetylsalicylic acid.
AlclometasoneThe metabolism of Vorapaxar can be decreased when combined with Alclometasone.
AlfuzosinThe metabolism of Vorapaxar can be decreased when combined with Alfuzosin.
AloxiprinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Aloxiprin.
AlprostadilAlprostadil may increase the anticoagulant activities of Vorapaxar.
AlteplaseThe risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Alteplase.
AmcinonideThe metabolism of Vorapaxar can be decreased when combined with Amcinonide.
Food Interactions
Not Available

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. [PubMed:20926621]
  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. [PubMed:25728646]
  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. [PubMed:22077816]
  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. [PubMed:25680760]
External Links
KEGG Drug
D09766
PubChem Compound
10077130
PubChem Substance
310264983
ChemSpider
8252668
BindingDB
50261110
ChEBI
82702
ChEMBL
CHEMBL493982
HET
VPX
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Vorapaxar
ATC Codes
B01AC26 — Vorapaxar
AHFS Codes
  • 20:12.18 — Platelet Aggregation Inhibitors
PDB Entries
3vw7
FDA label
Download (651 KB)
MSDS
Download (49.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAcute Coronary Syndromes (ACS)1
1, 2RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
2CompletedPreventionArterial Obstructive Diseases / Coronary Heart Disease (CHD)1
2CompletedTreatmentAtherosclerosis / Myocardial Infarction / Myocardial Ischemia1
2CompletedTreatmentCerebral Infarctions1
2CompletedTreatmentFistula / Fistula Function Maturation1
3CompletedPreventionAtherosclerosis / Cerebrovascular Accidents / Myocardial Infarction / Peripheral Arterial Disease (PAD) / Transient ischemia attacks1
3CompletedPreventionAtherosclerosis / Cerebrovascular Accidents / Myocardial Infarction / Transient ischemia attacks1
3TerminatedPreventionAtherosclerosis / Myocardial Infarction / Myocardial Ischemia1
4CompletedHealth Services ResearchCoronary Artery Disease / Myocardial Infarction / Peripheral Vascular Disease (PVD)1
4CompletedTreatmentHealthy Volunteers1
4Not Yet RecruitingHealth Services ResearchCoronary Artery Disease1
4RecruitingTreatmentDiabetes Mellitus (DM) / Myocardial Infarction / Peripheral Arterial Disease (PAD)1
4RecruitingTreatmentMyocardial Infarction1
4WithdrawnOtherPeripheral Artery Disease (PAD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral2.5 mg
Tablet, film coatedOral2.08 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7304078No2004-04-062024-04-06Us
US7235567No2001-06-132021-06-13Us
US7713999No2004-05-302024-05-30Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP5.39ChEMBL
Predicted Properties
PropertyValueSource
Water Solubility0.000787 mg/mLALOGPS
logP5.2ALOGPS
logP5.82ChemAxon
logS-5.8ALOGPS
pKa (Strongest Acidic)8ChemAxon
pKa (Strongest Basic)4.32ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area81.01 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity135.31 m3·mol-1ChemAxon
Polarizability54.8 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

Taxonomy

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
Naphthofuran / 3-phenylpyridine / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Gamma butyrolactone / Pyridine / Benzenoid
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, carbamate ester, pyridines, lactone, naphthofuran (CHEBI:82702)

Targets

Kind
Protein
Organism
Human
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. [PubMed:19715408]

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:28781465]
  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. [PubMed:28063023]
Kind
Protein
Organism
Human
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. [PubMed:28781465]
  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. [PubMed:28063023]

Drug created on February 09, 2015 15:24 / Updated on September 21, 2018 00:16