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Identification
NameVorapaxar
Accession NumberDB09030
TypeSmall Molecule
GroupsApproved
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
Zontivity
External Identifiers
  • MFCD16038876
  • SCH 530348
  • SCH-530348
  • SCH530348
  • ZCE93644N2
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zontivitytablet, film coated2.08 mg/1oralMerck Sharp & Dohme Corp.2014-05-08Not applicableUs
Zontivitytablet2.5 mgoralMerck Canada IncNot applicableNot applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Vorapaxar Sulfate
ThumbNot applicableDBSALT001104
Categories
UNIIZCE93644N2
CAS number618385-01-6
WeightAverage: 492.5817
Monoisotopic: 492.242435759
Chemical FormulaC29H33FN2O4
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthofurans
Sub ClassNot Available
Direct ParentNaphthofurans
Alternative Parents
Substituents
  • Naphthofuran
  • 3-phenylpyridine
  • Halobenzene
  • Fluorobenzene
  • Cyclohexylamine
  • Benzenoid
  • Pyridine
  • Gamma butyrolactone
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Oxolane
  • Lactone
  • Carboxylic acid ester
  • Oxacycle
  • Azacycle
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationVorapaxar 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.
PharmacodynamicsNot Available
Mechanism of actionVorapaxar 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.
Related Articles
AbsorptionAfter 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 bindingVorapaxar 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.

SubstrateEnzymesProduct
Vorapaxar
amine metabolite (M19)Details
Vorapaxar
monohydroxy-vorapaxar (M20)Details
Route of eliminationVorapaxar is primarily eliminated as its metabolite M19 through the feces (91.5%), and partially eliminated in the urine (8.5%).
Half lifeVorapaxar has an effective half life of 3-4 days and an apparent terminal half life of 8 days.
ClearanceNot Available
ToxicityThere 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 organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral2.5 mg
Tablet, film coatedoral2.08 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7235567 No2001-06-132021-06-13Us
US7304078 No2004-04-062024-04-06Us
Properties
StateSolid
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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesB01AC26
AHFS Codes
  • 20:12.18
PDB EntriesNot Available
FDA labelDownload (651 KB)
MSDSDownload (49.5 KB)
Interactions
Drug Interactions
Drug
AbciximabThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Abciximab.
AcenocoumarolThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Acenocoumarol.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Acetylsalicylic acid.
AlteplaseVorapaxar may increase the anticoagulant activities of Alteplase.
AnistreplaseVorapaxar may increase the anticoagulant activities of Anistreplase.
ApixabanThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Apixaban.
ArgatrobanThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Argatroban.
AtazanavirThe serum concentration of Vorapaxar can be increased when it is combined with Atazanavir.
BivalirudinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Bivalirudin.
BoceprevirThe serum concentration of Vorapaxar can be increased when it is combined with Boceprevir.
CarbamazepineThe serum concentration of Vorapaxar can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Vorapaxar can be increased when it is combined with Ceritinib.
Citric AcidThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Citric Acid.
ClarithromycinThe serum concentration of Vorapaxar can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Vorapaxar can be increased when it is combined with Cobicistat.
CollagenaseThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Collagenase.
Dabigatran etexilateThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Dabigatran etexilate.
DalteparinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Dalteparin.
DanaparoidThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Danaparoid.
DarunavirThe serum concentration of Vorapaxar can be increased when it is combined with Darunavir.
DasatinibDasatinib may increase the anticoagulant activities of Vorapaxar.
Deoxycholic AcidThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Deoxycholic Acid.
DesirudinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Desirudin.
DicoumarolThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Dicoumarol.
Edetic AcidThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Edetic Acid.
EdoxabanThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Edoxaban.
EnoxaparinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Enoxaparin.
EnzalutamideThe serum concentration of Vorapaxar can be decreased when it is combined with Enzalutamide.
Ethyl biscoumacetateThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Ethyl biscoumacetate.
Fondaparinux sodiumThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Fondaparinux sodium.
FosphenytoinThe serum concentration of Vorapaxar can be decreased when it is combined with Fosphenytoin.
GlucosamineGlucosamine may increase the antiplatelet activities of Vorapaxar.
HeparinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Heparin.
Ibritumomab tiuxetanThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Ibritumomab.
IbrutinibThe risk or severity of adverse effects can be increased when Ibrutinib is combined with Vorapaxar.
IdelalisibThe serum concentration of Vorapaxar can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Vorapaxar can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Vorapaxar can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Vorapaxar can be increased when it is combined with Ketoconazole.
LimaprostLimaprost may increase the antiplatelet activities of Vorapaxar.
MitotaneThe serum concentration of Vorapaxar can be decreased when it is combined with Mitotane.
NadroparinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Nadroparin.
NefazodoneThe serum concentration of Vorapaxar can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Vorapaxar can be increased when it is combined with Nelfinavir.
ObinutuzumabThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Obinutuzumab.
Omega-3 fatty acidsOmega-3 fatty acids may increase the antiplatelet activities of Vorapaxar.
Pentosan PolysulfateThe risk or severity of adverse effects can be increased when Pentosan Polysulfate is combined with Vorapaxar.
PentoxifyllinePentoxifylline may increase the antiplatelet activities of Vorapaxar.
PhenindioneThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Phenindione.
PhenobarbitalThe serum concentration of Vorapaxar can be decreased when it is combined with Phenobarbital.
PhenprocoumonThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Phenprocoumon.
PhenytoinThe serum concentration of Vorapaxar can be decreased when it is combined with Phenytoin.
PosaconazoleThe serum concentration of Vorapaxar can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of Vorapaxar can be decreased when it is combined with Primidone.
ReteplaseVorapaxar may increase the anticoagulant activities of Reteplase.
RidogrelVorapaxar may increase the anticoagulant activities of Ridogrel.
RifabutinThe serum concentration of Vorapaxar can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Vorapaxar can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Vorapaxar can be decreased when it is combined with Rifapentine.
RitonavirThe serum concentration of Vorapaxar can be increased when it is combined with Ritonavir.
RivaroxabanThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Rivaroxaban.
SaquinavirThe serum concentration of Vorapaxar can be increased when it is combined with Saquinavir.
St. John's WortThe serum concentration of Vorapaxar can be decreased when it is combined with St. John's Wort.
StreptokinaseVorapaxar may increase the anticoagulant activities of Streptokinase.
SulodexideThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Sulodexide.
TelaprevirThe serum concentration of Vorapaxar can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Vorapaxar can be increased when it is combined with Telithromycin.
TenecteplaseVorapaxar may increase the anticoagulant activities of Tenecteplase.
TinzaparinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Tinzaparin.
TipranavirTipranavir may increase the antiplatelet activities of Vorapaxar.
TositumomabThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Tositumomab.
TreprostinilThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Treprostinil.
UrokinaseVorapaxar may increase the anticoagulant activities of Urokinase.
Vitamin EVitamin E may increase the antiplatelet activities of Vorapaxar.
VoriconazoleThe serum concentration of Vorapaxar can be increased when it is combined with Voriconazole.
WarfarinThe risk or severity of adverse effects can be increased when Vorapaxar is combined with Warfarin.
Food InteractionsNot Available

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
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 ]
Comments
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Drug created on February 09, 2015 15:24 / Updated on July 29, 2016 01:53