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targets (3) enzymes (1)
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Identification
Name Dicumarol
Accession Number DB00266 (APRD00761)
Type small molecule
Groups approved
Description

An oral anticoagulant that interferes with the metabolism of vitamin K. It is also used in biochemical experiments as an inhibitor of reductases. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Bis-Hydroxycoumarin
Bishydroxycoumarin
Dicoumarin
Dicoumarol
Salts Not Available
Brand names
Name Company
Acadyl
Acavyl
Antitrombosin
Baracoumin
Cuma
Cumid
Dicoumal
Dicuman
Dicumaol R
Dicumarine
Dicumol
Dikumarol
Dufalone
Kumoran
Melitoxin
Temparin
Trombosan
First Prev Next Last
Brand mixtures Not Available
Categories
  • Anticoagulants
  • Enzyme Inhibitors
  • Uncoupling Agents
CAS number 66-76-2
Weight Average: 336.295
Monoisotopic: 336.063388116
Chemical Formula C19H12O6
InChI Key InChIKey=DOBMPNYZJYQDGZ-UHFFFAOYSA-N
InChI
InChI=1S/C19H12O6/c20-16-10-5-1-3-7-14(10)24-18(22)12(16)9-13-17(21)11-6-2-4-8-15(11)25-19(13)23/h1-8,20-21H,9H2
Plain Text
IUPAC Name
4-hydroxy-3-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2H-chromen-2-one
SMILES
OC1=C(CC2=C(O)C3=C(OC2=O)C=CC=C3)C(=O)OC2=C1C=CC=C2
Plain Text
Mass Spec show (9.73 KB)
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For decreasing blood clotting. Often used along with heparin for treatment of deep vein thrombosis.
Pharmacodynamics Dicumarol is an coumarin-like compound found in sweet clover. It is used as an oral anticoagulant and acts by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors (prothrombin and factors VII, IX, and X). It is also used in biochemical experiments as an inhibitor of reductases.
Mechanism of action Dicumarol 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 decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity LD50=233 mg/kg (orally in mice); LD50=250 mg/kg (orally in rats)
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00270 Dicumarol Pathway SMP00270
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
  • Abbott laboratories pharmaceutical products div
Packagers Not Available
Dosage forms
Form Route Strength
Tablet Oral
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 290 °C PhysProp
water solubility 128 mg/L Not Available
logP 2.07 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 6.62e-02 g/l ALOGPS
logP 1.54 ALOGPS
logP -1.6 ChemAxon
logS -3.7 ALOGPS
pKa (strongest acidic) -12 ChemAxon
pKa (strongest basic) -3.1 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 93.06 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 89.19 ChemAxon
polarizability 32.32 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Cullen JJ, Hinkhouse MM, Grady M, Gaut AW, Liu J, Zhang YP, Weydert CJ, Domann FE, Oberley LW: Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism. Cancer Res. 2003 Sep 1;63(17):5513-20. Pubmed
  2. Mironov AA, Colanzi A, Polishchuk RS, Beznoussenko GV, Mironov AA Jr, Fusella A, Di Tullio G, Silletta MG, Corda D, De Matteis MA, Luini A: Dicumarol, an inhibitor of ADP-ribosylation of CtBP3/BARS, fragments golgi non-compact tubular zones and inhibits intra-golgi transport. Eur J Cell Biol. 2004 Jul;83(6):263-79. Pubmed
  3. Abdelmohsen K, Stuhlmann D, Daubrawa F, Klotz LO: Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication. Arch Biochem Biophys. 2005 Feb 15;434(2):241-7. Pubmed
  4. Thanos CG, Liu Z, Reineke J, Edwards E, Mathiowitz E: Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride. Pharm Res. 2003 Jul;20(7):1093-100. Pubmed
External Links
Resource Link
KEGG Drug D03798 Link_out
KEGG Compound C00796 Link_out
BindingDB 35525 Link_out
ChEBI 4513 Link_out
ChEMBL 4513 Link_out
Therapeutic Targets Database DAP000768 Link_out
PharmGKB PA449298 Link_out
Wikipedia http://en.wikipedia.org/wiki/Dicumarol Link_out
ATC Codes
  • B01AA01
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (64.7 KB)
Interactions
Drug Interactions
Drug Interaction
Acetaminophen Acetaminophen may increase the anticoagulant effect of dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if acetaminophen is initiated, discontinued or dose changed.
Acetohexamide Dicumarol may increase the effect of sulfonylurea, acetohexamide.
Acetylsalicylic acid Acetylsalicylic acid increases effect of the anticoagulant, dicumarol.
Allopurinol Allopurinol may increase the anticoagulant effect of dicumarol.
Aminoglutethimide Aminoglutethimide may decrease the anticoagulant effect of dicumarol.
Amiodarone Amiodarone may increase the anticoagulant effect of dicumarol.
Amprenavir Amprenavir may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
Aprepitant Aprepitant may decrease the anticoagulant effect of dicumarol by decreasing its serum concentration.
Atazanavir The protease inhibitor, atazanavir, may increase the anticoagulant effect of dicumarol.
Azathioprine Azathioprine may decrease the anticoagulant effect of dicumarol.
Azithromycin Azithromycin may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
Betamethasone The corticosteroid, betamethasone, alters the anticoagulant effect of dicumarol.
Bosentan Bosentan may decrease the anticoagulant effect of dicumarol by increasing its metabolism.
Capecitabine Capecitabine may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
Carbamazepine Carbamazepine may decrease the anticoagulant effect of dicumarol by decreasing its serum concentration.
Cefotetan The cephalosporin, cefotetan, may increase the anticoagulant effect of dicumarol.
Cefoxitin The cephalosporin, cefoxitin, may increase the anticoagulant effect of dicumarol.
Ceftriaxone The cephalosporin, ceftriaxone, may increase the anticoagulant effect of dicumarol.
Celecoxib Celecoxib may increase the anticoagulant effect of dicumarol.
Chlorpropamide Dicumarol may increase the effect of sulfonylurea, chlorpropamide.
Cholestyramine The bile acid sequestrant, cholestyramine, may decrease the anticoagulant effect of dicumarol by decreasing its absorption.
Cimetidine Cimetidine may increase the anticoagulant effect of dicumarol.
Ciprofloxacin The quinolone antibiotic, ciprofloxacin, may increase the anticoagulant effect of dicumarol.
Cisapride Cisapride may increase the anticoagulant effect of dicumarol.
Citalopram The SSRI, citalopram, increases the effect of anticoagulant, dicumarol.
Clarithromycin The macrolide, clarithromycin, may increase the anticoagulant effect of dicumarol.
Clofibrate The fibrate increases the anticoagulant effect
Colestipol The bile acid sequestrant, colestipol, may decrease the anticoagulant effect of dicumarol by decreasing its absorption.
Cyclophosphamide The antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of dicumarol.
Danazol The androgen, danazol, may increase the anticoagulant effect of dicumarol.
Demeclocycline The tetracycline, demeclocycline, may increase the anticoagulant effect of dicumarol.
Dexamethasone The corticosteroid, dexamethasone, alters the anticoagulant effect of dicumarol.
Dextrothyroxine The thyroid hormone, dextrothyroxine, increase the anticoagulant effect of dicumarol.
Diclofenac The NSAID, diclofenac, may increase the anticoagulant effect of dicumarol.
Dicloxacillin Dicloxacillin may decrease the anticoagulant effect of dicumarol.
Diflunisal The NSAID, diflunisal, may increase the anticoagulant effect of dicumarol.
Disulfiram Disulfiram may increase the anticoagulant effect of dicumarol.
Doxycycline The tetracycline, doxycycline, may increase the anticoagulant effect of dicumarol.
Erythromycin The macrolide, erythromycin, may increase the anticoagulant effect of dicumarol..
Ethchlorvynol Ethchlorvynol may decrease the anticoagulant effect of dicumarol.
Ethinyl Estradiol Increased thrombotic risk due to estrogen
Etodolac The NSAID, etodolac, may increase the anticoagulant effect of dicumarol.
Etoricoxib Etoricoxib may increase the anticoagulant effect of dicumarol.
Fenofibrate Fenofibrate may increase the anticoagulant effect of dicumarol.
Fenoprofen The NSAID, fenoprofen, may increase the anticoagulant effect of dicumarol.
Fluconazole Fluconazole may increase the serum concentration of dicumarol by decreasing its metabolism.
Fludrocortisone The corticosteroid, fludrocortisone, alters the anticoagulant effect of dicumarol.
Fluorouracil The antineoplasic agent, fluorouracil, may increase the anticoagulant effect of dicumarol.
Fluoxetine The SSRI, fluoxetine, increases the effect of anticoagulant, dicumarol.
Fluoxymesterone The androgen, fluoxymesterone, may increase the anticoagulant effect of dicumarol.
Flurbiprofen The NSAID, flurbiprofen, may increase the anticoagulant effect of dicumarol.
Fluvastatin Fluvastatin may increase the anticoagulant effect of dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if fluvastatin if initiated, discontinued or dose changed.
Fluvoxamine Fluvoxamine may increase the anticoagulant effect of dicumarol by increasing its serum concentration.
Fosamprenavir The protease inhibitor, fosamprenavir, may increase the anticoagulant effect of dicumarol.
Fosphenytoin Increased hydantoin levels and risk of bleeding
Gefitinib Gefitinib may increase the anticoagulant effect of dicumarol.
Gemcitabine Gemcitabine may increase the anticoagulant effect of dicumarol.
Gemfibrozil Gemfibrozil may increase the anticoagulant effect of dicumarol.
Gliclazide Dicumarol may increase the effect of sulfonylurea, gliclazide.
Glutethimide Glutethimide may decrease the anticoagulant effect of dicumarol.
Glyburide Dicumarol may increase the effect of sulfonylurea, glibenclamide.
Griseofulvin Griseofulvin may decrease the anticoagulant effect of dicumarol.
Hydrocortisone The corticosteroid, hydrocortisone, alters the anticoagulant effect of dicumarol.
Ibuprofen The NSAID, ibuprofen, may increase the anticoagulant effect of dicumarol.
Imatinib Imatinib may increase the anticoagulant effect of dicumarol.
Indinavir The protease inhibitor, indinavir, may increase the anticoagulant effect of dicumarol.
Indomethacin The NSAID, indomethacin, may increase the anticoagulant effect of dicumarol.
Isoniazid Isoniazid may increase the anticoagulant effect of dicumarol.
Itraconazole Itraconazole may increase the anticoagulant effect of dicumarol.
Ketoconazole Ketoconazole may increase the anticoagulant effect of dicumarol.
Ketoprofen The NSAID, ketoprofen, may increase the anticoagulant effect of dicumarol.
Ketorolac The NSAID, ketorolac, may increase the anticoagulant effect of dicumarol.
Leflunomide Leflunomide may increase the anticoagulant effect of dicumarol.
Levamisole Levamisole may increase the anticoagulant effect of dicumarol.
Levofloxacin The quinolone antibiotic, levofloxacin, may increase the anticoagulant effect of dicumarol.
Levothyroxine The thyroid hormone, levothyroxine, increase the anticoagulant effect of dicumarol.
Lovastatin Lovastatin may increase the anticoagulant effect dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if lovastatin is initiated, discontinued or dose changed.
Lumiracoxib Lumiracoxib may increase the anticoagulant effect of dicumarol.
Medroxyprogesterone Medroxyprogesterone may increase the anticoagulant effect of dicumarol.
Mefenamic acid The NSAID, mefanamic acid, may increase the anticoagulant effect of dicumarol.
Mefloquine Mefloquine may increase the anticoagulant effect of dicumarol.
Meloxicam Meloxicam may increase the anticoagulant effect of dicumarol.
Mercaptopurine Mercaptopurine may decrease the anticoagulant effect of dicumarol.
Methimazole The antithyroid agent, methimazole, may decrease the anticoagulant effect of dicumarol.
Metronidazole Metronidazole may increase the anticoagulant effect of dicumarol.
Miconazole Miconazole may increase the serum concentration of dicumarol by decreasing its metabolism.
Minocycline The tetracycline, minocycline, may increase the anticoagulant effect of dicumarol.
Mitotane Mitotane may decrease the anticoagulant effect of dicumarol.
Moxifloxacin The quinolone antibiotic, moxifloxacin, may increase the anticoagulant effect of dicumarol.
Nabumetone The NSAID, nabumetone, may increase the anticoagulant effect of dicumarol.
Nalidixic Acid The quinolone antibiotic, nalidixic acid, may increase the anticoagulant effect of dicumarol.
Naproxen The NSAID, naproxen, may increase the anticoagulant effect of dicumarol.
Nelfinavir The protease inhibitor, nelfinavir, may increase the anticoagulant effect of dicumarol.
Nevirapine Nevirapine may decrease the anticoagulant effect of dicumarol.
Norfloxacin The quinolone antibiotic, norfloxacin, may increase the anticoagulant effect of dicumarol.
Ofloxacin The quinolone antibiotic, ofloxacin, may increase the anticoagulant effect of dicumarol.
Orlistat Orlistat may increase the anticoagulant effect of dicumarol.
Oxaprozin The NSAID, oxaprozin, may increase the anticoagulant effect of dicumarol.
Oxyphenbutazone The NSAID, oxyphenbutazone, may increase the anticoagulant effect of dicumarol.
Paroxetine The SSRI, paroxetine, increases the effect of anticoagulant, dicumarol.
Pentoxifylline Pentoxifylline may increase the anticoagulant effect of dicumarol.
Phenobarbital The barbiturate, phenobarbital, decreases the anticoagulant effect, dicumarol.
Phenylbutazone The NSAID, phenylbutazone, may increase the anticoagulant effect of dicumarol.
Phenytoin Increased hydantoin levels and risk of bleeding
Piroxicam The NSAID, piroxicam, may increase the anticoagulant effect of dicumarol.
Prednisolone The corticosteroid, prednisolone, alters the anticoagulant effect of dicumarol.
Prednisone The corticosteroid, prednisone, alters the anticoagulant effect of dicumarol.
Primidone The barbiturate, primidone, decreases the anticoagulant effect, dicumarol.
Propafenone Propafenone may increase the anticoagulant effect of dicumarol.
Propoxyphene Propoxyphene may increase the anticoagulant effect of dicumarol.
Propylthiouracil The anti-thyroid agent, propylthiouracil, may decrease the anticoagulant effect of dicumarol.
Quinidine Quinidine may increase the anticoagulant effect of dicumarol.
Quinine Quinine may increase the anticoagulant effect of dicumarol.
Ranitidine Ranitidine may increase the anticoagulant effect of dicumarol. (Conflicting evidence)
Rifabutin Rifabutin may decrease the anticoagulant effect of dicumarol.
Rifampin Rifampin may decrease the anticoagulant effect of dicumarol.
Telithromycin Telithromycin may increase the anticoagulant effect of dicumarol.
Tenoxicam The NSAID, tenoxicam, may increase the anticoagulant effect of dicumarol.
Testosterone The androgen may increase the anticoagulant effect of dicumarol.
Tetracycline Tetracycline may increase the anticoagulant effect of dicumarol.
Tigecycline Tigecycline may increase the anticoagulant effect of dicumarol.
Triamcinolone The corticosteroid, triamcinolone, alters the anticoagulant effect of dicumarol.
Food Interactions Not Available
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Wallin R, Patrick SD, Ballard JO: Vitamin K antagonism of coumarin intoxication in the rat. Thromb Haemost. 1986 Apr 30;55(2):235-9. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. NAD(P)H dehydrogenase [quinone] 1

Pharmacological action: unknown
Actions: inhibitor

The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis

Organism class: human
UniProt ID: P15559 Link_out
Gene: NQO1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen S, Wu K, Zhang D, Sherman M, Knox R, Yang CS: Molecular characterization of binding of substrates and inhibitors to DT-diaphorase: combined approach involving site-directed mutagenesis, inhibitor-binding analysis, and computer modeling. Mol Pharmacol. 1999 Aug;56(2):272-8. Pubmed
  2. Jaiswal AK: Characterization and partial purification of microsomal NADH:quinone oxidoreductases. Arch Biochem Biophys. 2000 Mar 1;375(1):62-8. Pubmed
  3. Joseph P, Jaiswal AK: A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C. Br J Cancer. 2000 Apr;82(7):1305-11. Pubmed
  4. Floreani M, Napoli E, Palatini P: Protective action of cardiac DT-diaphorase against menadione toxicity in guinea pig isolated atria. Biochem Pharmacol. 2000 Aug 15;60(4):601-5. Pubmed
  5. Arriagada C, Dagnino-Subiabre A, Caviedes P, Armero JM, Caviedes R, Segura-Aguilar J: Studies of aminochrome toxicity in a mouse derived neuronal cell line: is this toxicity mediated via glutamate transmission? Amino Acids. 2000;18(4):363-73. Pubmed
  6. Preusch PC, Smalley DM: Vitamin K1 2,3-epoxide and quinone reduction: mechanism and inhibition. Free Radic Res Commun. 1990;8(4-6):401-15. Pubmed

3. Quinone oxidoreductase

Pharmacological action: unknown
Actions: inhibitor

Does not have alcohol dehydrogenase activity. Binds NADP and acts through a one-electron transfer process. Orthoquinones are the best substrates. May act in the detoxification of xenobiotics

Organism class: human
UniProt ID: Q08257 Link_out
Gene: CRYZ Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Evans PJ: Decreased intracellular proteolysis correlates with the maintenance of a specific isoenzyme of cytochrome P-450. Cell Biol Int. 1999;23(2):117-24. Pubmed
  2. Audi SH, Bongard RD, Dawson CA, Siegel D, Roerig DL, Merker MP: Duroquinone reduction during passage through the pulmonary circulation. Am J Physiol Lung Cell Mol Physiol. 2003 Nov;285(5):L1116-31. Epub 2003 Jul 25. Pubmed
  3. Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y: The crystal structure of NADH quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry. 2006 May 23;45(20):6372-8. Pubmed
  4. Maser E, Gebel T, Netter KJ: Carbonyl reduction of metyrapone in human liver. Biochem Pharmacol. 1991 Dec 11;42 Suppl:S93-8. Pubmed
  5. Hao H, Wang G, Cui N, Li J, Xie L, Ding Z: Identification of a novel intestinal first pass metabolic pathway: NQO1 mediated quinone reduction and subsequent glucuronidation. Curr Drug Metab. 2007 Feb;8(2):137-49. 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. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19