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
Thumb
Synonyms
  • 2-Phenyl-1,3-diketohydrindene
  • 2-Phenyl-1,3-indandione
  • 2-Phenyl-1,3(2H)-indenedione
  • Fenindiona
  • Fenindione
  • Phenindion
  • Phénindione
  • 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.

TargetActionsOrganism
AVitamin K epoxide reductase complex subunit 1
inhibitor
Human
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
PathwayCategory
Phenindione Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Phenindione can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Phenindione is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Phenindione is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Phenindione can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Phenindione can be increased when used in combination with 18-methyl-19-nortestosterone.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Phenindione.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Phenindione.
3,5-diiodothyropropionic acid3,5-diiodothyropropionic acid may increase the anticoagulant activities of Phenindione.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Phenindione.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Phenindione is combined with 4-hydroxycoumarin.
Food Interactions
Not Available

References

General References
  1. Link [Link]
External Links
Human Metabolome Database
HMDB0014641
KEGG Compound
C07584
PubChem Compound
4760
PubChem Substance
46505018
ChemSpider
4596
BindingDB
50280157
ChEBI
8066
ChEMBL
CHEMBL711
Therapeutic Targets Database
DAP000769
PharmGKB
PA164784031
Wikipedia
Phenindione
ATC Codes
B01AA02 — Phenindione
MSDS
Download (62.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionAnticoagulation in Pregnancy1
3RecruitingPreventionAtrial Flutter / Intracranial Hemorrhage, Hypertensive / Intracranial Hemorrhages / Intraventricular Hemorrhage / Microhaemorrhage / Nonvalvular Atrial Fibrillation / Small Vessel Cerebrovascular Disease / Subarachnoid Hemorrhage / Subdural haematoma1

Pharmacoeconomics

Manufacturers
  • Sanofi aventis us llc
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)150 °CPhysProp
water solubility27 mg/L (at 20 °C)Not Available
logP2.90HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.023 mg/mLALOGPS
logP3.1ALOGPS
logP2.88ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)4.88ChemAxon
pKa (Strongest Basic)-7.5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area34.14 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity65.23 m3·mol-1ChemAxon
Polarizability23.24 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9816
Caco-2 permeable+0.7697
P-glycoprotein substrateNon-substrate0.7593
P-glycoprotein inhibitor INon-inhibitor0.5461
P-glycoprotein inhibitor IINon-inhibitor0.8381
Renal organic cation transporterNon-inhibitor0.833
CYP450 2C9 substrateNon-substrate0.8036
CYP450 2D6 substrateNon-substrate0.9024
CYP450 3A4 substrateNon-substrate0.6947
CYP450 1A2 substrateInhibitor0.9013
CYP450 2C9 inhibitorNon-inhibitor0.5714
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.7715
CYP450 3A4 inhibitorNon-inhibitor0.9141
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.598
Ames testAMES toxic0.7125
CarcinogenicityNon-carcinogens0.88
BiodegradationNot ready biodegradable0.8033
Rat acute toxicity3.1041 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9414
hERG inhibition (predictor II)Non-inhibitor0.9008
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-00di-4690000000-3b0da30c88d7d0ecf339
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot 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
Human
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
  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:17139284]
  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:17016423]
  3. 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]
  4. 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 November 02, 2018 04:45