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Identification
Name Acenocoumarol
Accession Number DB01418
Type small molecule
Groups approved
Description

Acenocoumarol is a coumarin derivative used as an anticoagulant. Coumarin derivatives inhibit the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of vitamin K-dependent clotting factors, II, VII, XI and X, and interferes with coagulation. Hematocrit, hemoglobin, international normalized ratio and liver panel should be monitored. Patients on acenocoumarol are prohibited from giving blood.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Acenocoumarin
  • Acenocoumarolum [INN-latin]
  • Nicoumalone
  • Nicumalon
  • Nitrophenylacetylethyl-4-hydroxycoumarine
  • Nitrovarfarian
  • Nitrowarfarin
Brand names
  • Ascumar
  • Mini-sintrom
  • Neositron
  • Sincoumar
  • Sinkumar
  • Sinthrom
  • Sinthrome
  • Sintrom (Paladin)
  • Syncoumar
  • Syncumar
  • Syntrom
  • Zotil
Brand name mixtures Not Available
Categories
  • Anticoagulants
  • Coumarin and Indandione Derivatives
CAS number 152-72-7
Weight Average: 353.3255
Monoisotopic: 353.089937217
Chemical Formula C19H15NO6
InChI Key InChIKey=WWBYDEQHYAEHLT-UHFFFAOYSA-N
InChI
InChI=1S/C19H15NO6/c1-11(21)10-15(12-6-8-13(9-7-12)20(24)25)17-18(22)14-4-2-3-5-16(14)26-19(17)23/h2-9,15,23H,10H2,1H3
Plain Text
IUPAC Name
2-hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-4H-chromen-4-one
SMILES
CC(=O)CC(C1=CC=C(C=C1)[N+]([O-])=O)C1=C(O)OC2=C(C=CC=C2)C1=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Chromones
Substructures
  • Hydroxy Compounds
  • Nitrobenzenes
  • Oxoazaniums
  • Benzene and Derivatives
  • Chromones
  • Nitro compounds
  • Heterocyclic compounds
  • Aromatic compounds
  • Phenols and Derivatives
  • Anilines
  • Ketones
Pharmacology
Indication For the treatment and prevention of thromboembolic diseases. More specifically, it is indicated for the for the prevention of cerebral embolism, deep vein thrombosis, pulmonary embolism, thromboembolism in infarction and transient ischemic attacks. It is used for the treatment of deep vein thrombosis and myocardial infarction.
Pharmacodynamics Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by acenocoumarol.
Mechanism of action Acenocoumarol 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 clotting factors, 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 resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
Absorption Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration.
Volume of distribution

The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively
Protein binding 98.7% protein bound, mainly to albumin
Metabolism

Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 1A2 6-Hydroxy-R-acenocoumarol 6-hydroxylation
Cytochrome P450 2C9 6-Hydroxy-R-acenocoumarol 6-hydroxylation
Cytochrome P450 2C9 7-Hydroxy-R-acenocoumarol 7-hydroxylation
Cytochrome P450 2C9 8-Hydroxy-R-acenocoumarol 8-hydroxylation
Cytochrome P450 2C19 6-Hydroxy-R-acenocoumarol 6-hydroxylation
Cytochrome P450 2C19 7-Hydroxy-R-acenocoumarol 7-hydroxylation
Cytochrome P450 2C19 8-Hydroxy-R-acenocoumarol 8-hydroxylation
Route of elimination Mostly via the kidney as metabolites
Half life 8 to 11 hours.
Clearance Not Available
Toxicity The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdosage, and the duration of treatment. Bleeding is the major sign of toxicity with oral anticoagulant drugs. The most frequent symptoms observed are: cutaneous bleeding (80%), haematuria (with renal colic) (52%), haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and bleeding into the joints. Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00269 Acenocoumarol Pathway SMP00269
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Tablet Oral 1 mg
Tablet Oral 4 mg
Prices
Unit description Cost Unit
Sintrom 4 mg Tablet 1.6 USD tablet
Sintrom 1 mg Tablet 0.51 USD tablet
Patents Not Available
Properties
State solid
Melting point 197 oC
Experimental Properties
Property Value Source
water solubility practically insoluble [MSDS] PhysProp
logP 1.98 [SANGSTER (1994)] PhysProp
Predicted Properties
Property Value Source
water solubility 1.05e-02 g/l ALOGPS
logP 2.55 ALOGPS
logP 3.46 ChemAxon Molconvert
logS -4.53 ALOGPS
pKa 19.39 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 109.42 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 103.31 ChemAxon Molconvert
polarizability 34.53 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Cesar JM, Garcia-Avello A, Navarro JL, Herraez MV: Aging and oral anticoagulant therapy using acenocoumarol. Blood Coagul Fibrinolysis. 2004 Oct;15(8):673-6. Pubmed
  2. Lengyel M: [Warfarin or acenocoumarol is better in the anticoagulant treatment of chronic atrial fibrillation?] Orv Hetil. 2004 Dec 26;145(52):2619-21. Pubmed
  3. Ufer M: Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet. 2005;44(12):1227-46. Pubmed
  4. Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA, Alberca I, Hermida J: The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol. 2006 Apr;133(2):183-7. Pubmed
  5. Girard P, Nony P, Erhardtsen E, Delair S, Ffrench P, Dechavanne M, Boissel JP: Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acenocoumarol. Thromb Haemost. 1998 Jul;80(1):109-13. Pubmed
External Links
Resource Link
KEGG Drug D07064 Link_out
PubChem Compound 9052 Link_out
PubChem Substance 46507631 Link_out
ChemSpider 8700 Link_out
ChEBI 53766 Link_out
ChEMBL 53766 Link_out
Therapeutic Targets Database DAP000772 Link_out
PharmGKB PA452632 Link_out
Drug Product Database 10383 Link_out
Wikipedia http://en.wikipedia.org/wiki/Acenocoumarol Link_out
ATC Codes
  • B01AA07
AHFS Codes
  • 20:12.04.08
PDB Entries Not Available
FDA label Not Available
MSDS show (125.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • High doses of vitamin A, C, E and K (e.g. avocado, green vegetables)
Targets

1. Vitamin K epoxide reductase complex subunit 1

Pharmacological action: yes
Actions: inhibitor

Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K

Organism class: human
UniProt ID: Q9BQB6 Link_out
Gene: VKORC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA: Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood. 2005 Jul 1;106(1):135-40. Epub 2005 Mar 24. Pubmed
  3. Gonzalez-Conejero R, Corral J, Roldan V, Ferrer F, Sanchez-Serrano I, Sanchez-Blanco JJ, Marin F, Vicente V: The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol. J Thromb Haemost. 2007 Aug;5(8):1701-6. Epub 2007 May 21. Pubmed
  4. Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA, Alberca I, Hermida J: The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol. 2006 Apr;133(2):183-7. Pubmed
  5. Rettie AE, Farin FM, Beri NG, Srinouanprachanh SL, Rieder MJ, Thijssen HH: A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9. Br J Clin Pharmacol. 2006 Nov;62(5):617-20. Epub 2006 Jul 21. Pubmed
  6. Schalekamp T, Brasse BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, van Wijk EM, Egberts AC, de Boer A: VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther. 2006 Jul;80(1):13-22. Pubmed
  7. 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 2C9

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Stehle S, Kirchheiner J, Lazar A, Fuhr U: Pharmacogenetics of oral anticoagulants: a basis for dose individualization. Clin Pharmacokinet. 2008;47(9):565-94. Pubmed
  3. Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA: Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood. 2005 Jul 1;106(1):135-40. Epub 2005 Mar 24. Pubmed
  4. Gonzalez-Conejero R, Corral J, Roldan V, Ferrer F, Sanchez-Serrano I, Sanchez-Blanco JJ, Marin F, Vicente V: The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol. J Thromb Haemost. 2007 Aug;5(8):1701-6. Epub 2007 May 21. Pubmed
  5. Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA, Alberca I, Hermida J: The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol. 2006 Apr;133(2):183-7. Pubmed
  6. Rettie AE, Farin FM, Beri NG, Srinouanprachanh SL, Rieder MJ, Thijssen HH: A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9. Br J Clin Pharmacol. 2006 Nov;62(5):617-20. Epub 2006 Jul 21. Pubmed
  7. Schalekamp T, Brasse BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, van Wijk EM, Egberts AC, de Boer A: VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther. 2006 Jul;80(1):13-22. Pubmed
  8. 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 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

3. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

4. Cytochrome P450 3A4

Actions: substrate

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ufer M: Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet. 2005;44(12):1227-46. Pubmed
  2. Morales-Molina JA, Arrebola MA, Robles PA, Mangana JC: Possible interaction between topical terbinafine and acenocoumarol. Ann Pharmacother. 2009 Nov;43(11):1911-2. Epub 2009 Oct 20. Pubmed
Transporters
Searched, but no transporters found.
Carriers

1. Serum albumin

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Fitos I, Visy J, Simonyi M, Hermansson J: Stereoselective distribution of acenocoumarol enantiomers in human plasma: chiral chromatographic analysis of the ultrafiltrates. Chirality. 1993;5(5):346-9. Pubmed
  2. Fitos I, Visy J, Magyar A, Kajtar J, Simonyi M: Inverse stereoselectivity in the binding of acenocoumarol to human serum albumin and to alpha 1-acid glycoprotein. Biochem Pharmacol. 1989 Jul 15;38(14):2259-62. Pubmed
  3. Otagiri M, Fleitman JS, Perrin JH: Investigations into the binding of phenprocoumon to albumin using fluorescence spectroscopy. J Pharm Pharmacol. 1980 Jul;32(7):478-82. Pubmed

2. Alpha-1-acid glycoprotein 1

Appears to function in modulating the activity of the immune system during the acute-phase reaction

UniProt ID: P02763 Link_out
Gene: ORM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Fitos I, Visy J, Simonyi M, Hermansson J: Stereoselective distribution of acenocoumarol enantiomers in human plasma: chiral chromatographic analysis of the ultrafiltrates. Chirality. 1993;5(5):346-9. Pubmed
  2. Fitos I, Visy J, Magyar A, Kajtar J, Simonyi M: Inverse stereoselectivity in the binding of acenocoumarol to human serum albumin and to alpha 1-acid glycoprotein. Biochem Pharmacol. 1989 Jul 15;38(14):2259-62. Pubmed
  3. 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
Drug created on July 24, 2007 02:32 / Updated on June 22, 2011 20:26

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.