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Identification
NameIsoflurophate
Accession NumberDB00677  (APRD00763)
TypeSmall Molecule
GroupsApproved, Withdrawn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
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
DiflupylNot Available
FloroprylMerck
FluoprylMerck
Brand mixturesNot Available
SaltsNot Available
Categories
UNII12UHW9R67N
CAS number55-91-4
WeightAverage: 184.1457
Monoisotopic: 184.066459031
Chemical FormulaC6H14FO3P
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganophosphorus compounds
ClassOrganic phosphoric acids and derivatives
Sub ClassPhosphate esters
Direct ParentPhosphate esters
Alternative Parents
Substituents
  • Phosphoric acid ester
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Pharmacology
IndicationFor use in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia.
PharmacodynamicsIsoflurophate 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 actionThe mechanism of isoflurophate's action involves the irreversible inhibition of cholinesterase.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySigns 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
Manufacturers
  • Merck and co inc
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateLiquid
Experimental Properties
PropertyValueSource
boiling point62 @ 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 RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

U.S. Patent 2,409,039.

General ReferencesNot Available
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57.7 KB)
Interactions
Drug Interactions
Drug
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Isoflurophate.
AlfuzosinThe serum concentration of Alfuzosin can be increased when it is combined with Isoflurophate.
AlprazolamThe serum concentration of Alprazolam can be increased when it is combined with Isoflurophate.
AminophyllineThe serum concentration of Aminophylline can be decreased when it is combined with Isoflurophate.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Isoflurophate.
AmoxapineThe serum concentration of Amoxapine can be increased when it is combined with Isoflurophate.
AtazanavirThe serum concentration of Atazanavir can be increased when it is combined with Isoflurophate.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Isoflurophate.
BoceprevirThe serum concentration of Isoflurophate can be decreased when it is combined with Boceprevir.
BromocriptineThe serum concentration of Bromocriptine can be increased when it is combined with Isoflurophate.
CarbamazepineThe metabolism of Isoflurophate can be increased when combined with Carbamazepine.
CisaprideThe serum concentration of Cisapride can be increased when it is combined with Isoflurophate.
ClarithromycinThe therapeutic efficacy of Clarithromycin can be decreased when used in combination with Isoflurophate.
ClomipramineThe serum concentration of Clomipramine can be increased when it is combined with Isoflurophate.
CyclophosphamideThe risk or severity of adverse effects can be increased when Isoflurophate is combined with Cyclophosphamide.
CyclosporineThe serum concentration of Cyclosporine can be increased when it is combined with Isoflurophate.
DarunavirThe serum concentration of Darunavir can be increased when it is combined with Isoflurophate.
DelavirdineThe serum concentration of Delavirdine can be decreased when it is combined with Isoflurophate.
DesipramineThe serum concentration of Desipramine can be increased when it is combined with Isoflurophate.
DesogestrelThe serum concentration of Desogestrel can be decreased when it is combined with Isoflurophate.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Isoflurophate.
DihydroergotamineThe serum concentration of Dihydroergotamine can be increased when it is combined with Isoflurophate.
DiltiazemThe metabolism of Diltiazem can be decreased when combined with Isoflurophate.
DoxepinThe serum concentration of Doxepin can be increased when it is combined with Isoflurophate.
EnfuvirtideThe serum concentration of Enfuvirtide can be increased when it is combined with Isoflurophate.
Ergoloid mesylateThe serum concentration of Ergoloid mesylate can be increased when it is combined with Isoflurophate.
ErgonovineThe serum concentration of Ergonovine can be increased when it is combined with Isoflurophate.
ErgotamineThe serum concentration of Ergotamine can be increased when it is combined with Isoflurophate.
Ethinyl EstradiolThe serum concentration of Ethinyl Estradiol can be decreased when it is combined with Isoflurophate.
Ethynodiol diacetateThe serum concentration of Ethynodiol can be decreased when it is combined with Isoflurophate.
EtravirineThe serum concentration of Etravirine can be decreased when it is combined with Isoflurophate.
FosamprenavirThe serum concentration of Fosamprenavir can be increased when it is combined with Isoflurophate.
ImipramineThe serum concentration of Imipramine can be increased when it is combined with Isoflurophate.
IndinavirThe serum concentration of Indinavir can be increased when it is combined with Isoflurophate.
LopinavirThe serum concentration of Lopinavir can be increased when it is combined with Isoflurophate.
LovastatinThe serum concentration of Lovastatin can be increased when it is combined with Isoflurophate.
MestranolThe serum concentration of Mestranol can be decreased when it is combined with Isoflurophate.
MidazolamThe serum concentration of Midazolam can be increased when it is combined with Isoflurophate.
NefazodoneThe serum concentration of Nefazodone can be increased when it is combined with Isoflurophate.
NelfinavirThe serum concentration of Nelfinavir can be increased when it is combined with Isoflurophate.
NorethisteroneThe serum concentration of Norethindrone can be decreased when it is combined with Isoflurophate.
NortriptylineThe serum concentration of Nortriptyline can be increased when it is combined with Isoflurophate.
PethidineThe risk or severity of adverse effects can be increased when Isoflurophate is combined with Pethidine.
PimozideThe serum concentration of Pimozide can be increased when it is combined with Isoflurophate.
ProtriptylineThe serum concentration of Protriptyline can be increased when it is combined with Isoflurophate.
RiociguatThe serum concentration of Riociguat can be increased when it is combined with Isoflurophate.
RitonavirThe serum concentration of Ritonavir can be increased when it is combined with Isoflurophate.
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Isoflurophate.
SaquinavirThe serum concentration of Saquinavir can be increased when it is combined with Isoflurophate.
SildenafilThe serum concentration of Sildenafil can be increased when it is combined with Isoflurophate.
SimeprevirThe serum concentration of Simeprevir can be increased when it is combined with Isoflurophate.
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Isoflurophate.
TacrolimusThe metabolism of Tacrolimus can be decreased when combined with Isoflurophate.
TemsirolimusThe risk or severity of adverse effects can be increased when Isoflurophate is combined with Temsirolimus.
TheophyllineThe serum concentration of Theophylline can be decreased when it is combined with Isoflurophate.
TipranavirThe serum concentration of Isoflurophate can be decreased when it is combined with Tipranavir.
TriazolamThe serum concentration of Triazolam can be increased when it is combined with Isoflurophate.
TrimipramineThe serum concentration of Trimipramine can be increased when it is combined with Isoflurophate.
Valproic AcidThe serum concentration of Valproic Acid can be decreased when it is combined with Isoflurophate.
VerapamilThe metabolism of Verapamil can be decreased when combined with Isoflurophate.
ZidovudineThe serum concentration of Zidovudine can be decreased when it is combined with Isoflurophate.
Food InteractionsNot Available

Targets

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
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
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 ]

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
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 ]
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Drug created on June 13, 2005 07:24 / Updated on May 02, 2014 15:42