Identification

Name
Isoflurophate
Accession Number
DB00677  (APRD00763)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

An irreversible cholinesterase inhibitor with actions similar to those of echothiophate. It is a powerful miotic used mainly in the treatment of glaucoma. Its vapor is highly toxic and it is recommended that only solutions in arachis oil be used therapeutically. (From Martindale, The Extra Pharmacopoeia, 29th ed, p1330)

Structure
Thumb
Synonyms
  • DFP
  • Diisopropoxyphosphoryl Fluoride
  • Diisopropyl fluorophosphate
  • Diisopropyl Fluorophosphonate
  • Diisopropyl Phosphofluoridate
  • Diisopropyl Phosphorofluoridate
  • Diisopropylfluorophosphate
  • Diisopropylfluorophosphoric acid ester
  • Diisopropylphosphofluoridate
  • Diisopropylphosphorofluoridate
  • Fluorodiisopropyl Phosphate
  • Fluorostigmine
  • Isofluorphate
  • Isoflurophate
  • Isoflurophosphate
  • Isopropyl fluophosphate
  • Isopropyl Phosphorofluoridate
  • Neoglaucit
  • O,O'-diisopropyl phosphoryl fluoride
International/Other Brands
Diflupyl / Floropryl (Merck) / Fluopryl (Merck)
Categories
UNII
12UHW9R67N
CAS number
55-91-4
Weight
Average: 184.1457
Monoisotopic: 184.066459031
Chemical Formula
C6H14FO3P
InChI Key
MUCZHBLJLSDCSD-UHFFFAOYSA-N
InChI
InChI=1S/C6H14FO3P/c1-5(2)9-11(7,8)10-6(3)4/h5-6H,1-4H3
IUPAC Name
bis(propan-2-yl) fluorophosphonate
SMILES
CC(C)OP(F)(=O)OC(C)C

Pharmacology

Indication

For use in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia.

Pharmacodynamics

Isoflurophate is used as ocular drops in the treatment of chronic glaucoma. Isoflurophate is an organophosphorus compound that acts as an irreversible cholinesterase inhibitor. As such, it displays parasympathomimetic effects. Isoflurophate is used in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia. They may also be used in the diagnosis of certain eye conditions, such as accommodative esotropia. Isoflurophate damages the acetylcholinesterase enzyme and is therefore irreversible, however, pralidoxime can displace organophosphates such as isoflurophate from acetylcholinesterase, but only if administered before isoflurophate damages (alkylates) the enzyme.

Mechanism of action

The mechanism of isoflurophate's action involves the irreversible inhibition of cholinesterase.

TargetActionsOrganism
AAcetylcholinesterase
inhibitor
Human
ACholinesterase
inhibitor
Human
USerotransferrinNot AvailableHuman
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

Signs of overdose include increased sweating, loss of bladder control, muscle weakness, nausea, vomiting, diarrhea, or stomach cramps or pain, shortness of breath, tightness in chest, or wheezing, slow or irregular heartbeat, unusual tiredness or weakness, watering of mouth.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when 16-Bromoepiandrosterone is combined with Isoflurophate.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when 19-norandrostenedione is combined with Isoflurophate.
5-androstenedioneThe risk or severity of adverse effects can be increased when 5-androstenedione is combined with Isoflurophate.
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Isoflurophate.
AcebutololIsoflurophate may increase the bradycardic activities of Acebutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Isoflurophate is combined with Acetylcholine.
AclidiniumThe therapeutic efficacy of Aclidinium can be decreased when used in combination with Isoflurophate.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Isoflurophate.
AlclometasoneThe therapeutic efficacy of Isoflurophate can be decreased when used in combination with Alclometasone.
AlcuroniumThe therapeutic efficacy of Alcuronium can be decreased when used in combination with Isoflurophate.
Food Interactions
Not Available

References

Synthesis Reference

U.S. Patent 2,409,039.

General References
Not Available
External Links
Human Metabolome Database
HMDB0014815
KEGG Drug
D00043
KEGG Compound
C00202
PubChem Compound
5936
PubChem Substance
46504499
ChemSpider
5723
BindingDB
50022772
ChEBI
17941
ChEMBL
CHEMBL1025
Therapeutic Targets Database
DAP000896
PharmGKB
PA164748933
Wikipedia
Isoflurophate
MSDS
Download (57.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedTreatmentHIV Infection Asymptomatic1
2CompletedNot AvailableChronic Iron Overload1
2RecruitingTreatmentParkinson's Disease (PD)1
2, 3Not Yet RecruitingTreatmentAmyotrophic Lateral Sclerosis (ALS)1
2, 3Unknown StatusTreatmentBeta-Thalassemia Major / Iron Hemosiderosis / Sickle Cell Disorders1
2, 3Unknown StatusTreatmentIron Chelation / Thalassemia Major (TM) / Vitamin c1
3CompletedTreatmentPantothenate Kinase-associated Neurodegeneration (PKAN)1
4CompletedNot AvailableHepatic Impairment1
4CompletedNot AvailableImpaired Renal Function1
4CompletedTreatmentBeta-Thalassemia / Thalassemia Major (TM)1
Not AvailableCompletedTreatmentBeta-Thalassemia Major1

Pharmacoeconomics

Manufacturers
  • Merck and co inc
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
boiling point (°C)62 @ 9mm, 46 @ 5mmU.S. Patent 2,409,039.
water solubility1.54E+004 mg/L (at 25 °C)MERCK INDEX (1996)
logP1.17CZERWINSKI,SE ET AL. (1998)
Predicted Properties
PropertyValueSource
Water Solubility6.78 mg/mLALOGPS
logP1.1ALOGPS
logP1.76ChemAxon
logS-1.4ALOGPS
pKa (Strongest Basic)-9.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.53 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity40.89 m3·mol-1ChemAxon
Polarizability16.75 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9971
Blood Brain Barrier+0.9803
Caco-2 permeable-0.5386
P-glycoprotein substrateNon-substrate0.8483
P-glycoprotein inhibitor INon-inhibitor0.7683
P-glycoprotein inhibitor IINon-inhibitor0.9518
Renal organic cation transporterNon-inhibitor0.9541
CYP450 2C9 substrateNon-substrate0.8393
CYP450 2D6 substrateNon-substrate0.8447
CYP450 3A4 substrateNon-substrate0.5232
CYP450 1A2 substrateNon-inhibitor0.8174
CYP450 2C9 inhibitorNon-inhibitor0.8396
CYP450 2D6 inhibitorNon-inhibitor0.9132
CYP450 2C19 inhibitorNon-inhibitor0.7248
CYP450 3A4 inhibitorNon-inhibitor0.8834
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9185
Ames testNon AMES toxic0.8082
CarcinogenicityCarcinogens 0.8124
BiodegradationNot ready biodegradable0.8938
Rat acute toxicity4.5346 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9572
hERG inhibition (predictor II)Non-inhibitor0.8508
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
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as phosphate esters. These are organic compounds containing phosphoric acid ester functional group, with the general structure R1P(=O)(R2)OR3. R1,R2 = O,N, or halogen atom; R3 = organyl group.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Organic phosphoric acids and derivatives
Sub Class
Phosphate esters
Direct Parent
Phosphate esters
Alternative Parents
Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Phosphoric acid ester / Organic oxygen compound / Organic oxide / Hydrocarbon derivative / Organooxygen compound / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
dialkyl phosphate (CHEBI:17941) / a small molecule (DIISOPROPYL-FLUOROPHOSPHATE)

Targets

Details
1. Acetylcholinesterase
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine hydrolase activity
Specific Function
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name
ACHE
Uniprot ID
P22303
Uniprot Name
Acetylcholinesterase
Molecular Weight
67795.525 Da
References
  1. Malatova Z, Gottlieb M, Marsala J: Depression of acetylcholinesterase synthesis following transient cerebral ischemia in rat: pharmacohistochemical and biochemical investigation. Gen Physiol Biophys. 1999 Mar;18(1):57-71. [PubMed:10378121]
  2. Quistad GB, Zhang N, Sparks SE, Casida JE: Phosphoacetylcholinesterase: toxicity of phosphorus oxychloride to mammals and insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid. Chem Res Toxicol. 2000 Jul;13(7):652-7. [PubMed:10898598]
  3. da Costa VL Jr, Lapa AJ, Godinho RO: Short- and long-term influences of calcitonin gene-related peptide on the synthesis of acetylcholinesterase in mammalian myotubes. Br J Pharmacol. 2001 May;133(2):229-36. [PubMed:11350858]
  4. Pang YP, Kollmeyer TM, Hong F, Lee JC, Hammond PI, Haugabouk SP, Brimijoin S: Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem Biol. 2003 Jun;10(6):491-502. [PubMed:12837382]
  5. Ashani Y, Gentry MK, Doctor BP: Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Biochemistry. 1990 Mar 13;29(10):2456-63. [PubMed:1692236]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Kamata R, Saito S, Suzuki T, Takewaki T, Kobayashi H: Correlation of binding sites for diisopropyl phosphorofluoridate with cholinesterase and neuropathy target esterase in membrane and cytosol preparations from hen. Neurotoxicology. 2001 Apr;22(2):203-14. [PubMed:11405252]
  2. Acey RA, Bailey S, Healy P, Jo C, Unger TF, Hudson RA: A butyrylcholinesterase in the early development of the brine shrimp (Artemia salina) larvae: a target for phthalate ester embryotoxicity? Biochem Biophys Res Commun. 2002 Dec 13;299(4):659-62. [PubMed:12459190]
  3. Pittel Z, Cohen S, Fisher A, Heldman E: Differential long-term effect of AF64A on [3H]ACh synthesis and release in rat hippocampal synaptosomes. Brain Res. 1992 Jul 17;586(1):148-51. [PubMed:1511344]
  4. Miller RB, Blank CL: Determination of serum cholinesterase activity by liquid chromatography with electrochemical detection. Anal Biochem. 1991 Aug 1;196(2):377-84. [PubMed:1776688]
  5. Kelly SS, Ferry CB, Bamforth JP: The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles. Br J Pharmacol. 1990 Apr;99(4):721-6. [PubMed:2361169]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transferrin receptor binding
Specific Function
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from si...
Gene Name
TF
Uniprot ID
P02787
Uniprot Name
Serotransferrin
Molecular Weight
77063.195 Da
References
  1. Li B, Schopfer LM, Grigoryan H, Thompson CM, Hinrichs SH, Masson P, Lockridge O: Tyrosines of human and mouse transferrin covalently labeled by organophosphorus agents: a new motif for binding to proteins that have no active site serine. Toxicol Sci. 2009 Jan;107(1):144-55. doi: 10.1093/toxsci/kfn211. Epub 2008 Oct 16. [PubMed:18930948]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Kamata R, Saito S, Suzuki T, Takewaki T, Kobayashi H: Correlation of binding sites for diisopropyl phosphorofluoridate with cholinesterase and neuropathy target esterase in membrane and cytosol preparations from hen. Neurotoxicology. 2001 Apr;22(2):203-14. [PubMed:11405252]
  2. Acey RA, Bailey S, Healy P, Jo C, Unger TF, Hudson RA: A butyrylcholinesterase in the early development of the brine shrimp (Artemia salina) larvae: a target for phthalate ester embryotoxicity? Biochem Biophys Res Commun. 2002 Dec 13;299(4):659-62. [PubMed:12459190]
  3. Pittel Z, Cohen S, Fisher A, Heldman E: Differential long-term effect of AF64A on [3H]ACh synthesis and release in rat hippocampal synaptosomes. Brain Res. 1992 Jul 17;586(1):148-51. [PubMed:1511344]
  4. Miller RB, Blank CL: Determination of serum cholinesterase activity by liquid chromatography with electrochemical detection. Anal Biochem. 1991 Aug 1;196(2):377-84. [PubMed:1776688]
  5. Kelly SS, Ferry CB, Bamforth JP: The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles. Br J Pharmacol. 1990 Apr;99(4):721-6. [PubMed:2361169]
  6. Masson P, Fortier PL, Albaret C, Froment MT, Bartels CF, Lockridge O: Aging of di-isopropyl-phosphorylated human butyrylcholinesterase. Biochem J. 1997 Oct 15;327 ( Pt 2):601-7. [PubMed:9359435]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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 colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Peeples ES, Schopfer LM, Duysen EG, Spaulding R, Voelker T, Thompson CM, Lockridge O: Albumin, a new biomarker of organophosphorus toxicant exposure, identified by mass spectrometry. Toxicol Sci. 2005 Feb;83(2):303-12. Epub 2004 Nov 3. [PubMed:15525694]
  2. Li B, Schopfer LM, Hinrichs SH, Masson P, Lockridge O: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assay for organophosphorus toxicants bound to human albumin at Tyr411. Anal Biochem. 2007 Feb 15;361(2):263-72. Epub 2006 Dec 4. [PubMed:17188226]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 12:52