Warfarin
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Basic Info
| Common Name | Warfarin(F04719) |
| 2D Structure | |
| Description | Warfarin is an anticoagulant drug normally used to prevent blood clot formation as well as migration. Although originally marketed as a pesticide (d-Con, Rodex, among others), Warfarin has since become the most frequently prescribed oral anticoagulant in North America. Warfarin has several properties that should be noted when used medicinally, including its ability to cross the placental barrier during pregnancy which can result in fetal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death. Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with warfarin use. Warfarin does not actually affect blood viscosity, rather, it inhibits vitamin-k dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors. |
| FRCD ID | F04719 |
| CAS Number | 81-81-2 |
| PubChem CID | 54678486 |
| Formula | C19H16O4 |
| IUPAC Name | 4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one |
| InChI Key | PJVWKTKQMONHTI-UHFFFAOYSA-N |
| InChI | InChI=1S/C19H16O4/c1-12(20)11-15(13-7-3-2-4-8-13)17-18(21)14-9-5-6-10-16(14)23-19(17)22/h2-10,15,21H,11H2,1H3 |
| Canonical SMILES | CC(=O)CC(C1=CC=CC=C1)C2=C(C3=CC=CC=C3OC2=O)O |
| Isomeric SMILES | CC(=O)CC(C1=CC=CC=C1)C2=C(C3=CC=CC=C3OC2=O)O |
| Wikipedia | Warfarin |
| Synonyms |
warfarin
Coumadin
81-81-2
Coumafene
Prothromadin
Coumafen
Zoocoumarin
Coumarins
Coumefene
Panwarfin
|
| Classifies |
Pollutant
Pesticide
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Phenylpropanoids and polyketides |
| Class | Coumarins and derivatives |
| Subclass | Hydroxycoumarins |
| Intermediate Tree Nodes | Not available |
| Direct Parent | 4-hydroxycoumarins |
| Alternative Parents | |
| Molecular Framework | Aromatic heteropolycyclic compounds |
| Substituents | 4-hydroxycoumarin - Benzopyran - 1-benzopyran - Pyranone - Monocyclic benzene moiety - Benzenoid - Pyran - Heteroaromatic compound - Vinylogous acid - Ketone - Lactone - Oxacycle - Organoheterocyclic compound - Organic oxygen compound - Carbonyl group - Hydrocarbon derivative - Organic oxide - Organooxygen compound - Aromatic heteropolycyclic compound |
| Description | This 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. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 308.333 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 4 |
| Complexity | 502 |
| Monoisotopic Mass | 308.105 |
| Exact Mass | 308.105 |
| XLogP | 2.7 |
| Formal Charge | 0 |
| Heavy Atom Count | 23 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 1 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB+ | 0.9124 |
| Human Intestinal Absorption | HIA+ | 0.9109 |
| Caco-2 Permeability | Caco2+ | 0.8867 |
| P-glycoprotein Substrate | Substrate | 0.5502 |
| P-glycoprotein Inhibitor | Non-inhibitor | 0.8782 |
| Non-inhibitor | 0.8382 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.8863 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.7130 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.6780 |
| CYP450 2D6 Substrate | Substrate | 0.5658 |
| CYP450 3A4 Substrate | Non-substrate | 0.6007 |
| CYP450 1A2 Inhibitor | Non-inhibitor | 0.7140 |
| CYP450 2C9 Inhibitor | Inhibitor | 0.7657 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9286 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.9161 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.8309 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.8785 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.8768 |
| Non-inhibitor | 0.9615 | |
| AMES Toxicity | Non AMES toxic | 0.6844 |
| Carcinogens | Non-carcinogens | 0.9352 |
| Fish Toxicity | High FHMT | 0.9555 |
| Tetrahymena Pyriformis Toxicity | High TPT | 0.9459 |
| Honey Bee Toxicity | High HBT | 0.6465 |
| Biodegradation | Not ready biodegradable | 0.7474 |
| Acute Oral Toxicity | I | 0.7767 |
| Carcinogenicity (Three-class) | Non-required | 0.5829 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -3.9526 | LogS |
| Caco-2 Permeability | 0.9288 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 4.1700 | LD50, mol/kg |
| Fish Toxicity | -0.4334 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | 0.8350 | pIGC50, ug/L |
MRLs
| Food | Product Code | Country | MRLs | Application Date | Notes |
|---|---|---|---|---|---|
| Other Poultry Animals,Edible Offal | Japan | 0.001ppm | |||
| Other Vegetables | Japan | 0.001ppm | |||
| Honey | Japan | 0.001ppm | |||
| Other Aquatic Animal | Japan | 0.001ppm | |||
| Crustaceans | Japan | 0.001ppm | |||
| Shelled Molluscas | Japan | 0.001ppm | |||
| Other Fish | Japan | 0.001ppm | |||
| Perciformes | Japan | 0.001ppm | |||
| Anguilliformes | Japan | 0.001ppm | |||
| Salmoniformes | Japan | 0.001ppm | |||
| Other Poultry,Eggs | Japan | 0.001ppm | |||
| Chicken,Eggs | Japan | 0.001ppm | |||
| Chicken,Edible Offal | Japan | 0.001ppm | |||
| Other Poultry Animals,Kidney | Japan | 0.001ppm | |||
| Chicken,Kidney | Japan | 0.001ppm | |||
| Other Poultry Animals,Liver | Japan | 0.001ppm | |||
| Chicken,Liver | Japan | 0.001ppm | |||
| Other Poultry Animals,Fat | Japan | 0.001ppm | |||
| Chicken,Fat | Japan | 0.001ppm | |||
| Other Poultry Animals,Muscle | Japan | 0.001ppm |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Potential cancer chemopreventive and anticancer constituents from the fruits ofFicus hispida L.f. (Moraceae). | J Ethnopharmacol | 2018 Mar 25 | 29197545 |
| Phenylpropanoids are key players in the antioxidant defense to ozone of European ash, Fraxinus excelsior. | Environ Sci Pollut Res Int | 2018 Mar | 27995504 |
| Coumarin: a novel player in microbial quorum sensing and biofilm formationinhibition. | Appl Microbiol Biotechnol | 2018 Mar | 29392389 |
| Ethnobotany of the genus Taraxacum-Phytochemicals and antimicrobial activity. | Phytother Res | 2018 Jul 24 | 30039597 |
| Vascular Calcification, Vitamin K and Warfarin Therapy - Possible or PlausibleConnection? | Basic Clin Pharmacol Toxicol | 2018 Jan | 28639365 |
| Evaluation of Aculeatin and Toddaculin Isolated from Toddalia asiatica as Anti-inflammatory Agents in LPS-Stimulated RAW264 Macrophages. | Biol Pharm Bull | 2018 | 29311475 |
| Use of direct oral anticoagulants for stroke prevention in elderly patients with nonvalvular atrial fibrillation. | J Am Assoc Nurse Pract | 2017 Sep | 28805310 |
| Safety and efficacy of rivaroxaban compared with warfarin in patients undergoing peripheral arterial procedures. | J Vasc Surg | 2017 Oct | 28712814 |
| Metabolic benefits of rivaroxaban in non-valvular atrial fibrillation patientsafter radiofrequency catheter ablation. | J Zhejiang Univ Sci B | 2017 Nov. | 29119732 |
| Toxicity of coumarins synthesized by Pechmann-Duisberg condensation againstDrosophila melanogaster larvae and antibacterial effects. | Food Chem Toxicol | 2017 Nov | 28576470 |
| Anticoagulation endpoints with clinical implementation of warfarinpharmacogenetic dosing in a real-world setting: A proposal for a newpharmacogenetic dosing approach. | Clin Pharmacol Ther | 2017 May | 28032893 |
| Angelica keiskei, an emerging medicinal herb with various bioactive constituents and biological activities. | Arch Pharm Res | 2017 Jun | 28439780 |
| Comparison of the safety and efficacy between 3-factor and 4-factor prothrombincomplex concentrates for the reversal of warfarin. | Am J Emerg Med | 2017 Jun | 28161220 |
| Omega-3 Fatty Acid Supplementation and Warfarin: A Lethal Combination inTraumatic Brain Injury. | J Trauma Nurs | 2017 Jan/Feb | 28033135 |
| Nuclease-aided target recycling signal amplification strategy for ochratoxin A monitoring. | Biosens Bioelectron | 2017 Jan 15 | 27542086 |
| Binding thermodynamics of synthetic dye Allura Red with bovine serum albumin. | Food Chem | 2017 Feb 15 | 27664607 |
| Improvement of time in therapeutic range with warfarin by pharmaceuticalintervention. | Int J Clin Pharm | 2017 Feb | 27905076 |
| Research on Chemical Composition and Biological Properties Including AntiquorumSensing Activity of Angelica pancicii Vandas Aerial Parts and Roots. | J Agric Food Chem | 2017 Dec 20 | 29129053 |
| Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in ContemporaryPractice: A Retrospective Cohort Study. | Ann Intern Med | 2017 Dec 19 | 29132153 |
| Development and Validation of Quantitative Ultraperformance LiquidChromatography-Tandem Mass Spectrometry Assay for Anticoagulant Rodenticides inLiver. | J Agric Food Chem | 2017 Aug 9 | 28699743 |
Targets
- General Function:
- Vitamin-k-epoxide reductase (warfarin-sensitive) activity
- Specific Function:
- 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. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.
- Gene Name:
- VKORC1
- Uniprot ID:
- Q9BQB6
- Molecular Weight:
- 18234.3 Da
- Mechanism of Action:
- Warfarin 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.
References
- Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
- General Function:
- Toxic substance binding
- Specific Function:
- 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. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
- Gene Name:
- ALB
- Uniprot ID:
- P02768
- Molecular Weight:
- 69365.94 Da
References
- Giannetti AM, Wong H, Dijkgraaf GJ, Dueber EC, Ortwine DF, Bravo BJ, Gould SE, Plise EG, Lum BL, Malhi V, Graham RA: Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449). J Med Chem. 2011 Apr 28;54(8):2592-601. doi: 10.1021/jm1008924. Epub 2011 Mar 25. [21438527 ]
- Specific Function:
- Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
- Gene Name:
- ORM1
- Uniprot ID:
- P02763
- Molecular Weight:
- 23511.38 Da
References
- Herve F, Duche JC, d'Athis P, Marche C, Barre J, Tillement JP: Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. [8946472 ]
- General Function:
- Steroid 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 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.
- Gene Name:
- CYP2C9
- Uniprot ID:
- P11712
- Molecular Weight:
- 55627.365 Da
References
- Afzelius L, Zamora I, Masimirembwa CM, Karlen A, Andersson TB, Mecucci S, Baroni M, Cruciani G: Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors. J Med Chem. 2004 Feb 12;47(4):907-14. [14761192 ]
- Specific Function:
- Keratin-binding protein required for epithelial cell polarization. Involved in apical junction complex (AJC) assembly via its interaction with PARD3. Required for ciliogenesis.
- Gene Name:
- FBF1
- Uniprot ID:
- Q8TES7
- Molecular Weight:
- 125445.19 Da
References
- Krishnakumar SS, Panda D: Spatial relationship between the prodan site, Trp-214, and Cys-34 residues in human serum albumin and loss of structure through incremental unfolding. Biochemistry. 2002 Jun 11;41(23):7443-52. [12044178 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
- Gene Name:
- NR1I2
- Uniprot ID:
- O75469
- Molecular Weight:
- 49761.245 Da
References
- Rulcova A, Prokopova I, Krausova L, Bitman M, Vrzal R, Dvorak Z, Blahos J, Pavek P: Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes. J Thromb Haemost. 2010 Dec;8(12):2708-17. doi: 10.1111/j.1538-7836.2010.04036.x. [20735727 ]
- General Function:
- Serine-type endopeptidase activity
- Specific Function:
- Likely to represent a ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RXXX[KR]R consensus motif.
- Gene Name:
- PCSK7
- Uniprot ID:
- Q16549
- Molecular Weight:
- 86246.44 Da
References
- de Oliveira CM, Silva GH, Regasini LO, Flausino O, Lopez SN, Abissi BM, Berlinck RG, Sette LD, Bonugli-Santos RC, Rodrigues A, Bolzani Vda S, Araujo AR: Xylarenones C-E from an endophytic fungus isolated from Alibertia macrophylla. J Nat Prod. 2011 Jun 24;74(6):1353-7. doi: 10.1021/np1005983. Epub 2011 Apr 21. [21510613 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).
- Gene Name:
- PPARG
- Uniprot ID:
- P37231
- Molecular Weight:
- 57619.58 Da
References
- Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
- General Function:
- Vitamin-k-epoxide reductase (warfarin-sensitive) activity
- Specific Function:
- Involved in vitamin K metabolism. Can reduce inactive vitamin K 2,3-epoxide to active vitamin K (in vitro), and may contribute to vitamin K-mediated protection against oxidative stress. Plays a role in vitamin K-dependent gamma-carboxylation of Glu residues in target proteins.
- Gene Name:
- VKORC1L1
- Uniprot ID:
- Q8N0U8
- Molecular Weight:
- 19835.425 Da
- Mechanism of Action:
- Warfarin 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.
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
- 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 homeostasis, inflammation and wound healing.
- Gene Name:
- F2
- Uniprot ID:
- P00734
- Molecular Weight:
- 70036.295 Da
- Mechanism of Action:
- Warfarin 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.
References
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]