Identification

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Name
Edoxudine
Accession Number
DB13421
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Edoxudine is a deoxythymidine analog with activity against herpes simplex virus. It is a potent and selective inhibitor of herpes simplex virus type 1 and 2. The obtained product is an antiviral ointment.7 The activity of edoxudine against herpes simplex virus was first recognized in 1967. It was later recognized to be effective in vivo in a preclinical model of keratitis caused by herpes virus.1 It was developed by McNeil Pharmaceutical and approved by Health Canada on December 31, 1992. This medication was later discontinued from the market in 1998.6

Structure
Thumb
Synonyms
  • 2'-Deoxy-5-ethyluridine
  • 5-Ethyl-2'-deoxyuridine
External IDs
ORF 15817 / ORF-15817 / RWJ 15817 / RWJ-15817
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Virostat Cream 3%Cream3 %TopicalMcneil Pharmaceutical, Division Of Ortho Mcneil Inc.1992-12-311998-06-05Canada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Categories
UNII
15ZQM81Y3R
CAS number
15176-29-1
Weight
Average: 256.258
Monoisotopic: 256.105921623
Chemical Formula
C11H16N2O5
InChI Key
XACKNLSZYYIACO-DJLDLDEBSA-N
InChI
InChI=1S/C11H16N2O5/c1-2-6-4-13(11(17)12-10(6)16)9-3-7(15)8(5-14)18-9/h4,7-9,14-15H,2-3,5H2,1H3,(H,12,16,17)/t7-,8+,9+/m0/s1
IUPAC Name
5-ethyl-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione
SMILES
CCC1=CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O

Pharmacology

Indication

Edoxudine was used in Europe, in the form of a topical antiviral, for the treatment of human herpes keratitis.1 Human herpes keratitis is an inflammation of the cornea in the eye caused by herpes simplex virus infection. This infection is a cause of significant morbidity whose incidence is significantly increased in the presence of recurrent infection and it can even produce corneal blindness.3

Edoxudine 3% cream was also indicated for the treatment of dermal herpes simplex virus.1 This virus can produce an infection ubiquitously and it is highly contagious. There are two types of herpes virus, type 1 that is mainly transmitted by oral-to-oral contact and type 2 that is sexually transmitted.8

Pharmacodynamics

In reports, it has been indicated that at antivirally active doses, edoxudine is phosphorylated to a much greater extent by hepatitis-infected cells when compared to mock-infected cells. Once phosphorylated, edoxudine is more highly incorporated into viral DNA than cellular DNA. The level of incorporation into viral DNA highly seems to be correlated with the concentration of edoxudine. The suppression of viral DNA synthesis caused a shutoff of viral replication and the viral titration is significantly reduced.2The effect of edoxudine is also proven to reduce significantly the lesion area produced by the viral activity to an even 44% reduction.1

Mechanism of action

Edoxudine is a potent inhibitor of the replication of herpes simplex virus type 1 and 2. For the activation of this drug, the action of viral thymidine kinase is required to phosphorylate this molecule in order to form the 5'-monophosphate derivative. Then, it is needed to be further phosphorylated by cellular enzymes until the formation of the 5'-triphosphate derivative which is a competitive inhibitor of the viral-coded DNA polymerase.7 The advantage of edoxudine is that it is highly selective, this characteristic can be seen by its preferential phosphorylation in herpes-infected cells and its preferential incorporation into viral DNA.2

TargetActionsOrganism
ADNA polymerase
inhibitor
Human herpesvirus 1
Absorption

Edoxudine cream is able to penetrate the skin in a very rapid manner. This easy penetration allows edoxudine to have a greater activity when compared with other topical antivirals that have better antiviral activity in vitro.1 In preclinical trials in mice, after intravenous administration of edoxudine, the mean residence time was 25 min. Edoxudine presented a bioavailability of 49% with a Cmax and tmax of 2.4 mcg/g and 31.1 min respectively. The AUC in plasma of edoxudine is significantly higher when administered orally when compared with intravenous administration.4

Volume of distribution

This pharmacokinetic property is not available.

Protein binding

The plasma protein binding of edoxudine is very low and it is reported to be of about 7%. It is mainly found in a bound state to albumin.5

Metabolism

In preclinical trials it has been reported that edoxudine presents a biotransformation marked by a cleavage of the glycoside bond. The degradation of edoxudine, after oral administration, seems to be processed by the activity of phosphorylases presented in the gastrointestinal tract and by pre-systemic metabolism.4

Route of elimination
Not Available
Half life

In preclinical trials on mice, after intravenous administration, edoxudine presented a very short distribution half-life of 1.4 min. In the same trials, the elimination half-life was reported to be of 24.1 min.4

Clearance

The plasma clearance of edoxudine is reported to be 85 ml/min.5

Toxicity

Edoxudine is been reported to present cytotoxic effects and some degree of DNA incorporation in human leukemic cells and PHA-stimulated lymphocytes in vitro.9

Affected organisms
  • Herpes simplex virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Spruance SL, Freeman DJ, Sheth NV: Comparison of topically applied 5-ethyl-2'-deoxyuridine and acyclovir in the treatment of cutaneous herpes simplex virus infection in guinea pigs. Antimicrob Agents Chemother. 1985 Jul;28(1):103-6. [PubMed:4037770]
  2. De Clercq E, Bernaerts R: Specific phosphorylation of 5-ethyl-2'-deoxyuridine by herpes simplex virus-infected cells and incorporation into viral DNA. J Biol Chem. 1987 Nov 5;262(31):14905-11. [PubMed:2822705]
  3. Remeijer L, Osterhaus A, Verjans G: Human herpes simplex virus keratitis: the pathogenesis revisited. Ocul Immunol Inflamm. 2004 Dec;12(4):255-85. doi: 10.1080/092739490500363. [PubMed:15621867]
  4. Cheraghali AM, Knaus EE, Wiebe LI: Bioavailability and pharmacokinetic parameters for 5-ethyl-2'-deoxyuridine. Antiviral Res. 1994 Dec;25(3-4):259-67. [PubMed:7710272]
  5. Cheraghali AM, Kumar R, Wang L, Knaus EE, Wiebe LI: Synthesis, biotransformation, pharmacokinetics, and antiviral properties of 5-ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers. Biochem Pharmacol. 1994 Apr 29;47(9):1615-25. [PubMed:8185676]
  6. Health Canada [Link]
  7. National Cancer Institute [Link]
  8. WHO [Link]
  9. Wikigenes [Link]
External Links
PubChem Compound
66377
PubChem Substance
347829299
ChemSpider
59752
BindingDB
50132292
ChEBI
135051
ChEMBL
CHEMBL318153
Wikipedia
Edoxudine
ATC Codes
D06BB09 — Edoxudine
MSDS
Download (52.5 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CreamTopical3 %
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)153 ºCEPA
water solubility>38.4 mcg/mlBurnham Center for Chemical Genomics.
logP-1.09Cheraghali M., et al. (1994). Biochemical Pharmacology.
pKa9.98'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility61.4 mg/mLALOGPS
logP-0.73ALOGPS
logP-0.67ChemAxon
logS-0.62ALOGPS
pKa (Strongest Acidic)9.95ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area99.1 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity60.01 m3·mol-1ChemAxon
Polarizability24.93 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Pyrimidine 2'-deoxyribonucleosides
Direct Parent
Pyrimidine 2'-deoxyribonucleosides
Alternative Parents
Pyrimidones / Hydropyrimidines / Vinylogous amides / Tetrahydrofurans / Heteroaromatic compounds / Ureas / Secondary alcohols / Lactams / Oxacyclic compounds / Azacyclic compounds
show 5 more
Substituents
Pyrimidine 2'-deoxyribonucleoside / Pyrimidone / Hydropyrimidine / Pyrimidine / Heteroaromatic compound / Tetrahydrofuran / Vinylogous amide / Lactam / Secondary alcohol / Urea
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human herpesvirus 1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
3'-5' exonuclease activity
Gene Name
DNApol
Uniprot ID
Q91CQ6
Uniprot Name
DNA polymerase
Molecular Weight
136474.73 Da
References
  1. National Cancer Institute [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
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. Cheraghali AM, Kumar R, Wang L, Knaus EE, Wiebe LI: Synthesis, biotransformation, pharmacokinetics, and antiviral properties of 5-ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers. Biochem Pharmacol. 1994 Apr 29;47(9):1615-25. [PubMed:8185676]

Drug created on June 23, 2017 14:41 / Updated on June 04, 2019 07:52