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
Structure for Vorapaxar (DB09030)
- 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.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prevention of Cardiovascular event •••••••••••• Prevention of Cardiovascular event •••••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism AProteinase-activated receptor 1 antagonistHumans - 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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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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Vorapaxar can be increased when it is combined with Abametapir. Abatacept The metabolism of Vorapaxar can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Abciximab. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Vorapaxar. Abrocitinib The risk or severity of bleeding and thrombocytopenia can be increased when Vorapaxar is combined with Abrocitinib. - 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Vorapaxar sulfate IN66038E6C 705260-08-8 NQRYCIGCIAWEIC-CKLVGUEFSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zontivity Tablet, film coated 2.08 mg/1 Oral Merck Sharp & Dohme Corp. 2014-05-08 2016-09-13 US 
Zontivity Tablet, film coated 2.08 mg/1 Oral WraSer Pharmaceuticals, LLC 2022-09-21 Not applicable US Zontivity Tablet, film coated 2.08 mg/1 Oral Aralez Pharmaceuticals Us Inc. 2014-05-08 Not applicable US Zontivity Tablet 2.5 mg Oral Xspire Pharma, Llc Not applicable Not applicable Canada 
Categories
- ATC Codes
- B01AC26 — Vorapaxar
- Drug Categories
- Anticoagulants
- Antiplatelet agents
- Blood and Blood Forming Organs
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 Substrates
- Hematologic Agents
- P-glycoprotein inhibitors
- Platelet Aggregation Inhibitors Excl. Heparin
- Protease-activated Receptor-1 Antagonist
- Protease-activated Receptor-1 Antagonists
- Receptor, PAR-1, antagonists & inhibitors
- Receptors, Thrombin, antagonists & inhibitors
- 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
- 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]
- 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]
- 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]
- 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]
- External Links
- KEGG Drug
- D09765
- PubChem Compound
- 10077130
- PubChem Substance
- 310264983
- ChemSpider
- 8252668
- BindingDB
- 50261110
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Health Services Research Coronary Artery Disease (CAD) / Myocardial Infarction / Peripheral Vascular Disease Patient 1 4 Completed Treatment Diabetes Mellitus / Myocardial Infarction / Peripheral Arterial Disease (PAD) 1 4 Completed Treatment Healthy Subjects (HS) 1 4 Completed Treatment Myocardial Infarction 1 4 Not Yet Recruiting Health Services Research Coronary Artery Disease (CAD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 2.5 mg Tablet, film coated Oral 2 MG Tablet, film coated Oral 2.08 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7304078 No 2007-12-04 2024-04-06 US US7235567 No 2007-06-26 2021-06-13 US US7713999 No 2010-05-11 2024-05-30 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 5.39 ChEMBL - Predicted Properties
Property Value Source Water Solubility 0.000654 mg/mL ALOGPS logP 4.9 ALOGPS logP 5.04 Chemaxon logS -5.9 ALOGPS pKa (Strongest Acidic) 14.78 Chemaxon pKa (Strongest Basic) 4.32 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 77.52 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 134.52 m3·mol-1 Chemaxon Polarizability 53.85 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0006-0000900000-3b52c9b3186ff5e27a3d Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00vi-1000900000-5f24df50b8c1224578ce Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-5001900000-e4e80184dc1d910a00dd Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0005-0000900000-d7a72e63e2f28ff2ef92 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-002f-2000900000-d3e21896a66b72102c43 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0gwf-0215900000-e95475e2552c8b470eb9 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 210.25874 predictedDeepCCS 1.0 (2019) [M+H]+ 212.15416 predictedDeepCCS 1.0 (2019) [M+Na]+ 218.22939 predictedDeepCCS 1.0 (2019)
Targets
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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
- 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
- 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]
- 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
- 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]
- 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 at February 09, 2015 22:24 / Updated at February 20, 2024 23:54