You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NamePhenprocoumon
Accession NumberDB00946  (APRD00228)
TypeSmall Molecule
GroupsApproved
Description

Coumarin derivative that acts as a long acting oral anticoagulant. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
3-(1-Phenylpropyl)-4-hydroxycoumarinNot AvailableNot Available
3-(1'-Phenyl-propyl)-4-oxycoumarinNot AvailableNot Available
3-(alpha-Ethylbenzyl)-4-hydroxycoumarinNot AvailableNot Available
3-(alpha-Phenylpropyl)-4-hydroxycoumarinNot AvailableNot Available
4-Hydroxy-3-(1-phenylpropyl)-2H-1-benzopyran-2-oneNot AvailableNot Available
4-Hydroxy-3-(1-phenylpropyl)-2H-chromen-2-oneNot AvailableNot Available
FenprocumonNot AvailableNot Available
FenprocumoneNot AvailableDCIT
PhenprocoumarolNot AvailableNot Available
PhenprocoumaroleNot AvailableNot Available
PhenprocoumoneNot AvailableINN
PhenprocoumonumNot AvailableNot Available
PhenprocumoneNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
FalithromNot Available
MarcoumarNot Available
MarcumarNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number435-97-2
WeightAverage: 280.3178
Monoisotopic: 280.109944378
Chemical FormulaC18H16O3
InChI KeyDQDAYGNAKTZFIW-UHFFFAOYSA-N
InChI
InChI=1S/C18H16O3/c1-2-13(12-8-4-3-5-9-12)16-17(19)14-10-6-7-11-15(14)21-18(16)20/h3-11,13,19H,2H2,1H3
IUPAC Name
4-hydroxy-3-(1-phenylpropyl)-2H-chromen-2-one
SMILES
CCC(C1=CC=CC=C1)C1=C(O)C2=C(OC1=O)C=CC=C2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 4-hydroxycoumarins. These are coumarins that contain one or more hydroxyl groups attached to C4-position the coumarin skeleton.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassCoumarins and derivatives
Sub ClassHydroxycoumarins
Direct Parent4-hydroxycoumarins
Alternative Parents
Substituents
  • 4-hydroxycoumarin
  • 1-benzopyran
  • Benzopyran
  • Phenylpropane
  • Pyranone
  • Benzenoid
  • Pyran
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Vinylogous acid
  • Lactone
  • Oxacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationUsed for the prevention and treatment of thromboembolic disease including venous thrombosis, thromboembolism, and pulmonary embolism as well as for the prevention of ischemic stroke in patients with atrial fibrillation (AF).
PharmacodynamicsPhenprocoumon, a coumarin anticoagulant, thins the blood by antagonizing vitamin K which is required for the production of clotting factors in the liver. Anticoagulants such as phenprocoumon have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage (damage caused by an inadequate blood supply to an organ or part of the body). However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Mechanism of actionPhenprocoumon inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
AbsorptionBioavailability is close to 100%
Volume of distributionNot Available
Protein binding99%
Metabolism

Phenprocoumon is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites. Cytochrome P450 2C9 is the principal form of human liver P-450 responsible for metabolism.

SubstrateEnzymesProduct
Phenprocoumon
4'-Hydroxy-R-phenprocoumonDetails
Phenprocoumon
6-Hydroxy-R-phenprocoumonDetails
Phenprocoumon
8-Hydroxy-R-phenprocoumonDetails
Phenprocoumon
7-Hydroxy-R-phenprocoumonDetails
Route of eliminationNot Available
Half life5-6 days
ClearanceNot Available
Toxicity50=500 mg/kg. Symptoms of overdose includes suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries).
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Phenprocoumon Action PathwayDrug actionSMP00271
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.992
Blood Brain Barrier+0.8992
Caco-2 permeable+0.8924
P-glycoprotein substrateSubstrate0.5545
P-glycoprotein inhibitor INon-inhibitor0.8579
P-glycoprotein inhibitor IINon-inhibitor0.8896
Renal organic cation transporterNon-inhibitor0.8798
CYP450 2C9 substrateNon-substrate0.6832
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.687
CYP450 1A2 substrateInhibitor0.6462
CYP450 2C9 substrateInhibitor0.7572
CYP450 2D6 substrateNon-inhibitor0.9555
CYP450 2C19 substrateNon-inhibitor0.5
CYP450 3A4 substrateNon-inhibitor0.9032
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6013
Ames testNon AMES toxic0.8363
CarcinogenicityNon-carcinogens0.9044
BiodegradationNot ready biodegradable0.8477
Rat acute toxicity3.1784 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9105
hERG inhibition (predictor II)Non-inhibitor0.9479
Pharmacoeconomics
Manufacturers
  • Organon usa inc
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point179.5 °CPhysProp
water solubility12.9 mg/LNot Available
logP3.62HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.0486 mg/mLALOGPS
logP3.81ALOGPS
logP3.74ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)6.44ChemAxon
pKa (Strongest Basic)-6.5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area46.53 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity81.64 m3·mol-1ChemAxon
Polarizability29.92 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (10.9 KB)
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ATC CodesB01AA04
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Vitamin K epoxide reductase complex subunit 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vitamin K epoxide reductase complex subunit 1 Q9BQB6 Details

References:

  1. Schalekamp T, Brasse BP, Roijers JF, van Meegen E, van der Meer FJ, van Wijk EM, Egberts AC, de Boer A: VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther. 2007 Feb;81(2):185-93. Epub 2006 Dec 27. Pubmed
  2. Reitsma PH, van der Heijden JF, Groot AP, Rosendaal FR, Buller HR: A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med. 2005 Oct;2(10):e312. Epub 2005 Oct 11. Pubmed
  3. Thijssen HH, Baars LG: Microsomal warfarin binding and vitamin K 2,3-epoxide reductase. Biochem Pharmacol. 1989 Apr 1;38(7):1115-20. Pubmed
  4. Thijssen HH, Baars LG, Vervoort-Peters HT: Vitamin K 2,3-epoxide reductase: the basis for stereoselectivity of 4-hydroxycoumarin anticoagulant activity. Br J Pharmacol. 1988 Nov;95(3):675-82. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Schalekamp T, Brasse BP, Roijers JF, van Meegen E, van der Meer FJ, van Wijk EM, Egberts AC, de Boer A: VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther. 2007 Feb;81(2):185-93. Epub 2006 Dec 27. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: no

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Niedner R, von Oettingen U, Meyer F: [The reciprocal actions of phenprocoumon (Marcumar) with human serum albumin, erythrocytes and blood] Int J Clin Pharmacol Biopharm. 1975 Dec;12(4):446-57. Pubmed
  2. Fitos I, Visy J, Simonyi M: Species-dependency in chiral-drug recognition of serum albumin studied by chromatographic methods. J Biochem Biophys Methods. 2002 Dec 31;54(1-3):71-84. Pubmed
  3. Fitos I, Simonyi M: Stereoselective effect of phenprocoumon enantiomers on the binding of benzodiazepines to human serum albumin. Chirality. 1992;4(1):21-3. Pubmed
  4. Rehse K, Fiedler B: [Determination of the protein binding of drugs by continuous ultrafiltration. 9. Comparison of the binding of nonsteroid antirheumatics to human serum albumin and their interaction with phenprocoumon] Arch Pharm (Weinheim). 1989 Apr;322(4):241-3. Pubmed
  5. Niedner R, von Oettingen U, Meyer F: [Binding of phenprocoumarol (Marcumar) to human albumin] Int J Clin Pharmacol. 1973 Oct;8(2):160-6. Pubmed

2. Alpha-1-acid glycoprotein 1

Kind: protein

Organism: Human

Pharmacological action: no

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details

References:

  1. Otagiri M, Maruyama T, Imai T, Imamura Y: Fluorescent investigations of binding of phenprocoumon to alpha 1-acid glycoprotein. J Pharm Sci. 1987 Aug;76(8):646-9. Pubmed
  2. Hazai E, Visy J, Fitos I, Bikadi Z, Simonyi M: Selective binding of coumarin enantiomers to human alpha1-acid glycoprotein genetic variants. Bioorg Med Chem. 2006 Mar 15;14(6):1959-65. Epub 2005 Nov 15. Pubmed

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on March 03, 2014 21:17