Identification

Name
Betrixaban
Accession Number
DB12364  (DB06601)
Type
Small Molecule
Groups
Approved, Investigational
Description

Betrixaban is a non-vitamin K oral anticoagulant whose action is driven by the competitive and reversible inhibition of the factor Xa [1]. It was selected among all lead compounds due to its low hERG channel affinity while sustaining its factor Xa inhibition capacity [3]. Betrixaban, now developed by Portola Pharmaceuticals Inc., is prescribed as a venous thromboembolism (VTE) prophylactic for adult patients with moderate to severe restricted motility or with other risks for VTE [2]. VTE can be manifested as deep vein thrombosis or pulmonary embolism and it is a leading cause of preventable death in hospitalized patients [4].

Structure
Thumb
Synonyms
  • Betrixaban
  • N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide
  • N-(5-chloropyridin-2-yl)-2-[[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino]-5-methoxybenzamide
External IDs
PRT-054021 / PRT054021
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BevyxxaCapsule, gelatin coated40 mg/1OralPortola Pharmaceuticals, Inc.2017-07-07Not applicableUs
BevyxxaCapsule, gelatin coated80 mg/1OralPortola Pharmaceuticals, Inc.2017-07-07Not applicableUs
International/Other Brands
BEVYXXA (Portola Pharmaceuticals Inc.)
Categories
UNII
74RWP7W0J9
CAS number
330942-05-7
Weight
Average: 451.91
Monoisotopic: 451.1411173
Chemical Formula
C23H22ClN5O3
InChI Key
XHOLNRLADUSQLD-UHFFFAOYSA-N
InChI
InChI=1S/C23H22ClN5O3/c1-29(2)21(25)14-4-6-15(7-5-14)22(30)27-19-10-9-17(32-3)12-18(19)23(31)28-20-11-8-16(24)13-26-20/h4-13,25H,1-3H3,(H,27,30)(H,26,28,31)
IUPAC Name
N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylcarbamimidoyl)benzamido]-5-methoxybenzamide
SMILES
COC1=CC=C(NC(=O)C2=CC=C(C=C2)C(=N)N(C)C)C(=C1)C(=O)NC1=CC=C(Cl)C=N1

Pharmacology

Indication

Betrixaban is indicated for prophylaxis of venous thromboembolism (VTE) in conditions of moderate to severe restricted mobility or in patients that qualify as in risk of VTE.

Associated Conditions
Pharmacodynamics

Betrixaban is an oral anticoagulant that excerts its action by preventing thrombin generation without having a direct effect on platelet aggregation [5].

Mechanism of action

Betrixaban is a cofactor-independent direct inhibitor of the Factor Xa and inhibits free and prothrombinase-bound Factor Xa [1].

TargetActionsOrganism
ACoagulation factor X
inhibitor
Human
Absorption

Betrixaban presents a rapid absorption at a dose of 80 mg. Its peak plasma concentration is registered within 3-4 hours after oral administration in healthy humans. The oral bioavailability is 34% and it can be reduced with consumption of high fat food [4].

Volume of distribution

The apparent volume of distribution os 32 L/kg [Label].

Protein binding

Betrixaban is reported to be present a proteing binding of about 60% [4].

Metabolism

One of the major characteristics of Betrixaban is its minimal hepatic metabolism (< 1%), preventing potential accumulation with liver impariment. Unchanged Betrixaban is the main form found in human plasma, followed by two hydolitic CYP-independent inactive metabolites (15-18%). The minimal hepatic metabolism produces an unlikely drug-to-drug interaction with inhibitors or agonists of CYP450 [4].

Route of elimination

Betrixaban is reported to present mainly a gastrointestinal elimination route, it has been shown that even 85% of it gets disposed in the feces and only 11% of it can be found in the urine [1].

Half life

Betrixaban presents a long half-life of between 19-27 hours [1].

Clearance

Betrixaban presents a minimal renal clearance (being 5-7% of the administered dose) [4].

Toxicity

Betrixaban presents a minimal hepatotoxicity, which is the main adverse effect found in this class of drugs. Some of the major adverse effects of Betrixaban are bleeding or hypersensitivity [4].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Betrixaban can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when (R)-warfarin is combined with Betrixaban.
(S)-WarfarinThe risk or severity of bleeding can be increased when (S)-Warfarin is combined with Betrixaban.
1-TestosteroneThe therapeutic efficacy of Betrixaban can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Betrixaban can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Betrixaban.
4-HydroxytestosteroneThe therapeutic efficacy of Betrixaban can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Betrixaban can be increased when used in combination with 5beta-dihydrotestosterone.
6-Deoxyerythronolide BThe metabolism of Betrixaban can be decreased when combined with 6-Deoxyerythronolide B.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Betrixaban.
Food Interactions
Not Available

References

General References
  1. Turpie AG: New oral anticoagulants in atrial fibrillation. Eur Heart J. 2008 Jan;29(2):155-65. Epub 2007 Dec 19. [PubMed:18096568]
  2. Connolly SJ, Eikelboom J, Dorian P, Hohnloser SH, Gretler DD, Sinha U, Ezekowitz MD: Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J. 2013 May;34(20):1498-505. doi: 10.1093/eurheartj/eht039. Epub 2013 Mar 13. [PubMed:23487517]
  3. Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY: Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2179-85. doi: 10.1016/j.bmcl.2009.02.111. Epub 2009 Mar 3. [PubMed:19297154]
  4. Chan NC, Bhagirath V, Eikelboom JW: Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51. doi: 10.2147/VHRM.S63060. eCollection 2015. [PubMed:26170684]
  5. Cabral KP, Ansell JE: The role of factor Xa inhibitors in venous thromboembolism treatment. Vasc Health Risk Manag. 2015 Jan 30;11:117-23. doi: 10.2147/VHRM.S39726. eCollection 2015. [PubMed:25673997]
External Links
PubChem Compound
10275777
PubChem Substance
347828616
ChemSpider
18981107
BindingDB
50249298
ChEBI
140421
ChEMBL
CHEMBL512351
Wikipedia
Betrixaban
FDA label
Download (548 KB)
MSDS
Download (24.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealth Volunteers1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedOtherHealthy Volunteers1
1CompletedPreventionHepatic Impairment1
1CompletedTreatmentImpaired Renal Function1
1RecruitingTreatmentProphylaxis of Venous Thromboembolic Events1
2CompletedPreventionThromboembolism1
2CompletedTreatmentAtrial Flutter / Nonvalvular Atrial Fibrillation1
2CompletedTreatmentNonvalvular Atrial Fibrillation1
3CompletedPreventionVenous Thromboembolism (VTE)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, gelatin coatedOral40 mg/1
Capsule, gelatin coatedOral80 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8557852No2013-10-152028-09-08Us
US6376515No2002-04-232020-09-15Us
US8691847No2014-04-082020-09-15Us
US9629831No2017-04-252020-09-15Us
US9555023No2017-01-312026-11-07Us
US8404724No2013-03-262031-03-29Us
US8987463No2015-03-242030-12-28Us
US7598276No2009-10-062026-11-08Us
US6835739No2004-12-282020-09-15Us
US8518977No2013-08-272020-09-15Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)200-212 ºCVincent, et al. Crystalline forms of a Factor Xa inhibitor. Patent application number WO 2012031017 A1
water solubility2.5-2.7 mg/mlVincent, et al. Crystalline forms of a Factor Xa inhibitor. Patent application number WO 2012031017 A1
Predicted Properties
PropertyValueSource
Water Solubility0.0163 mg/mLALOGPS
logP2.86ALOGPS
logP3.03ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)11.63ChemAxon
pKa (Strongest Basic)10.91ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area107.41 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity138.29 m3·mol-1ChemAxon
Polarizability47.62 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
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 benzanilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with a benzene ring. They have the general structure RNC(=O)R', where R,R'= benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Anilides
Direct Parent
Benzanilides
Alternative Parents
Benzamides / Methoxyanilines / Anisoles / Phenoxy compounds / Benzoyl derivatives / Methoxybenzenes / Alkyl aryl ethers / Aryl chlorides / Pyridines and derivatives / Imidolactams
show 10 more
Substituents
Benzanilide / Benzamide / Benzoic acid or derivatives / Methoxyaniline / Anisole / Phenoxy compound / Benzoyl / Phenol ether / Methoxybenzene / Alkyl aryl ether
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name
F10
Uniprot ID
P00742
Uniprot Name
Coagulation factor X
Molecular Weight
54731.255 Da
References
  1. Connolly SJ, Eikelboom J, Dorian P, Hohnloser SH, Gretler DD, Sinha U, Ezekowitz MD: Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J. 2013 May;34(20):1498-505. doi: 10.1093/eurheartj/eht039. Epub 2013 Mar 13. [PubMed:23487517]
  2. Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY: Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2179-85. doi: 10.1016/j.bmcl.2009.02.111. Epub 2009 Mar 3. [PubMed:19297154]
  3. Chan NC, Bhagirath V, Eikelboom JW: Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51. doi: 10.2147/VHRM.S63060. eCollection 2015. [PubMed:26170684]
  4. Cabral KP, Ansell JE: The role of factor Xa inhibitors in venous thromboembolism treatment. Vasc Health Risk Manag. 2015 Jan 30;11:117-23. doi: 10.2147/VHRM.S39726. eCollection 2015. [PubMed:25673997]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Chan NC, Bhagirath V, Eikelboom JW: Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51. doi: 10.2147/VHRM.S63060. eCollection 2015. [PubMed:26170684]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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
References
  1. Chan NC, Bhagirath V, Eikelboom JW: Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51. doi: 10.2147/VHRM.S63060. eCollection 2015. [PubMed:26170684]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Chan NC, Bhagirath V, Eikelboom JW: Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51. doi: 10.2147/VHRM.S63060. eCollection 2015. [PubMed:26170684]

Drug created on October 20, 2016 16:05 / Updated on December 16, 2018 06:59