Phenindione
Identification
- Name
- Phenindione
- Accession Number
- DB00498 (APRD00166)
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
An indandione that has been used as an anticoagulant. Phenindione has actions similar to warfarin, but it is now rarely employed because of its higher incidence of severe adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p234)
- Structure
Structure for Phenindione (DB00498)
- Synonyms
- 2-phenyl-1,3-diketohydrindene
- 2-Phenyl-1,3-indandione
- 2-phenyl-1,3(2H)-Indenedione
- Fenindiona
- Fenindione
- Phenindion
- Phénindione
- Phenindione
- Phenindionum
- PID
- International/Other Brands
- Dindevan (Sigma) / Fenindion (Souriree) / Phenindione (Goldshield) / Soluthrombine (Cooper)
- Categories
- UNII
- 5M7Y6274ZE
- CAS number
- 83-12-5
- Weight
- Average: 222.2387
Monoisotopic: 222.068079564 - Chemical Formula
- C15H10O2
- InChI Key
- NFBAXHOPROOJAW-UHFFFAOYSA-N
- InChI
- InChI=1S/C15H10O2/c16-14-11-8-4-5-9-12(11)15(17)13(14)10-6-2-1-3-7-10/h1-9,13H
- IUPAC Name
- 2-phenyl-2,3-dihydro-1H-indene-1,3-dione
- SMILES
- O=C1C(C(=O)C2=CC=CC=C12)C1=CC=CC=C1
Pharmacology
- Indication
For the treatment of pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, mural thrombosis, and thrombophili. Also used for anticoagulant prophylaxis.
- Pharmacodynamics
Phenindione thins the blood by antagonizing vitamin K which is required for the production of clotting factors in the liver. Anticoagulants such as Phenindione 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. Phenindione has actions similar to warfarin, but it is now rarely employed because of its higer incidence of severe adverse effects.
- Mechanism of action
Phenindione 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.
Target Actions Organism AVitamin K epoxide reductase complex subunit 1 inhibitorHumans - Absorption
Absorbed slowly from the gastrointestinal tract.
- Volume of distribution
- Not Available
- Protein binding
88%
- Metabolism
Hepatic.
- Route of elimination
- Not Available
- Half life
5-10 hours
- Clearance
- Not Available
- Toxicity
Oral, mouse: LD50 = 175 mg/kg; Oral, rat: LD50 = 163 mg/kg.
- Affected organisms
- Humans and other mammals
- Pathways
Pathway Category Phenindione Action Pathway Drug action - Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Unlock Additional Data(1,2,6,7-3H)Testosterone (1,2,6,7-3H)Testosterone may increase the anticoagulant activities of Phenindione. (R)-warfarin The risk or severity of bleeding can be increased when Phenindione is combined with (R)-warfarin. (S)-Warfarin The risk or severity of bleeding can be increased when Phenindione is combined with (S)-Warfarin. 1-Testosterone 1-Testosterone may increase the anticoagulant activities of Phenindione. 18-methyl-19-nortestosterone 18-methyl-19-nortestosterone may increase the anticoagulant activities of Phenindione. 2,5-Dimethoxy-4-ethylthioamphetamine The risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Phenindione. 25-desacetylrifapentine The risk or severity of bleeding can be increased when 25-desacetylrifapentine is combined with Phenindione. 3,5-Diiodotyrosine 3,5-Diiodotyrosine may increase the anticoagulant activities of Phenindione. 4-Bromo-2,5-dimethoxyamphetamine The risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Phenindione. 4-hydroxycoumarin The risk or severity of bleeding can be increased when Phenindione is combined with 4-hydroxycoumarin. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionAction
An effect category for each drug interaction. Know how this interaction affects the subject drug.
Learn more
- Food Interactions
- Not Available
References
- General References
- Link [Link]
- External Links
- Human Metabolome Database
- HMDB0014641
- KEGG Drug
- D08354
- KEGG Compound
- C07584
- PubChem Compound
- 4760
- PubChem Substance
- 46505018
- ChemSpider
- 4596
- BindingDB
- 50280157
- RxNav
- 8130
- ChEBI
- 8066
- ChEMBL
- CHEMBL711
- ZINC
- ZINC000100004862
- Therapeutic Targets Database
- DAP000769
- PharmGKB
- PA164784031
- Wikipedia
- Phenindione
- ATC Codes
- B01AA02 — Phenindione
- MSDS
- Download (62.6 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Prevention Anticoagulation in Pregnancy 1 3 Recruiting Prevention Atrial Fibrillation (AF) / Flutter, Atrial / Intracranial Hemorrhage, Hypertensive / Intracranial Hemorrhages / Intraventricular Hemorrhage / Microhaemorrhage / Small Vessel Cerebrovascular Disease / Subarachnoid Hemorrhage / Subdural haematoma 1 Not Available Active Not Recruiting Not Available Atrial Fibrillation (AF) 1
Pharmacoeconomics
- Manufacturers
- Sanofi aventis us llc
- Packagers
- Not Available
- Dosage forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 150 °C PhysProp water solubility 27 mg/L (at 20 °C) Not Available logP 2.90 HANSCH,C ET AL. (1995) - Predicted Properties
Property Value Source Water Solubility 0.023 mg/mL ALOGPS logP 3.1 ALOGPS logP 2.88 ChemAxon logS -4 ALOGPS pKa (Strongest Acidic) 4.88 ChemAxon pKa (Strongest Basic) -7.5 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 2 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 34.14 Å2 ChemAxon Rotatable Bond Count 1 ChemAxon Refractivity 65.23 m3·mol-1 ChemAxon Polarizability 23.24 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9816 Caco-2 permeable + 0.7697 P-glycoprotein substrate Non-substrate 0.7593 P-glycoprotein inhibitor I Non-inhibitor 0.5461 P-glycoprotein inhibitor II Non-inhibitor 0.8381 Renal organic cation transporter Non-inhibitor 0.833 CYP450 2C9 substrate Non-substrate 0.8036 CYP450 2D6 substrate Non-substrate 0.9024 CYP450 3A4 substrate Non-substrate 0.6947 CYP450 1A2 substrate Inhibitor 0.9013 CYP450 2C9 inhibitor Non-inhibitor 0.5714 CYP450 2D6 inhibitor Non-inhibitor 0.9231 CYP450 2C19 inhibitor Non-inhibitor 0.7715 CYP450 3A4 inhibitor Non-inhibitor 0.9141 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.598 Ames test AMES toxic 0.7125 Carcinogenicity Non-carcinogens 0.88 Biodegradation Not ready biodegradable 0.8033 Rat acute toxicity 3.1041 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9414 hERG inhibition (predictor II) Non-inhibitor 0.9008
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Mass Spectrum (Electron Ionization) MS splash10-00di-4690000000-3b0da30c88d7d0ecf339 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available 1H NMR Spectrum 1D NMR Not Applicable 13C NMR Spectrum 1D NMR Not Applicable
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as indanediones. These are compounds containing an indane ring bearing two ketone groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Indanes
- Sub Class
- Indanones
- Direct Parent
- Indanediones
- Alternative Parents
- Aryl alkyl ketones / Beta-diketones / Benzene and substituted derivatives / Organic oxides / Hydrocarbon derivatives
- Substituents
- Indanedione / Aryl alkyl ketone / Aryl ketone / 1,3-diketone / 1,3-dicarbonyl compound / Monocyclic benzene moiety / Ketone / Organic oxygen compound / Organic oxide / Hydrocarbon derivative
- Molecular Framework
- Aromatic homopolycyclic compounds
- External Descriptors
- aromatic ketone, beta-diketone (CHEBI:8066)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- 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...
- Gene Name
- VKORC1
- Uniprot ID
- Q9BQB6
- Uniprot Name
- Vitamin K epoxide reductase complex subunit 1
- Molecular Weight
- 18234.3 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
- 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:17016423]
- Mentre F, Pousset F, Comets E, Plaud B, Diquet B, Montalescot G, Ankri A, Mallet A, Lechat P: Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients. Clin Pharmacol Ther. 1998 Jan;63(1):64-78. [PubMed:9465843]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Drug created on June 13, 2005 07:24 / Updated on May 02, 2020 03:16
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