Edoxudine
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Identification
- Summary
Edoxudine is a deoxythymidine analog used to treat herpetic keratitis.
- Generic Name
- Edoxudine
- DrugBank Accession Number
- DB13421
- Background
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
- Type
- Small Molecule
- Groups
- Approved, Investigational, Withdrawn
- Structure
- Weight
- Average: 256.258
Monoisotopic: 256.105921623 - Chemical Formula
- C11H16N2O5
- Synonyms
- 2'-Deoxy-5-ethyluridine
- 5-Ethyl-2'-deoxyuridine
- Edoxudine
- External IDs
- ORF 15817
- ORF-15817
- RWJ 15817
- RWJ-15817
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
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- 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
Target Actions Organism AThymidine kinase, cytosolic inhibitorHumans ADNA polymerase inhibitorHuman 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
- Adverse Effects
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- Toxicity
Not Available
- Pathways
- Not Available
- 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.Not Available
- Food Interactions
- Not Available
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Virostat Cream 3% Cream 3 % Topical Mcneil Pharmaceutical, Division Of Ortho Mcneil Inc. 1992-12-31 1998-06-05 Canada
Categories
- ATC Codes
- D06BB09 — Edoxudine
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Alcohol / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Lactam / Organic nitrogen compound / Organic oxide / Organic oxygen compound show 13 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Herpes simplex virus
Chemical Identifiers
- UNII
- 15ZQM81Y3R
- CAS number
- 15176-29-1
- 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
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Cheraghali AM, Knaus EE, Wiebe LI: Bioavailability and pharmacokinetic parameters for 5-ethyl-2'-deoxyuridine. Antiviral Res. 1994 Dec;25(3-4):259-67. [Article]
- 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. [Article]
- Health Canada [Link]
- National Cancer Institute [Link]
- WHO [Link]
- External Links
- PubChem Compound
- 66377
- PubChem Substance
- 347829299
- ChemSpider
- 59752
- BindingDB
- 50132292
- 49428
- ChEBI
- 135051
- ChEMBL
- CHEMBL318153
- ZINC
- ZINC000003956771
- Wikipedia
- Edoxudine
- MSDS
- Download (52.5 KB)
Clinical Trials
- Clinical Trials
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Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Cream Topical 3 % - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 153 ºC EPA water solubility >38.4 mcg/ml Burnham Center for Chemical Genomics. logP -1.09 Cheraghali M., et al. (1994). Biochemical Pharmacology. pKa 9.98 'MSDS' - Predicted Properties
Property Value Source Water Solubility 61.4 mg/mL ALOGPS logP -0.73 ALOGPS logP -0.67 Chemaxon logS -0.62 ALOGPS pKa (Strongest Acidic) 9.95 Chemaxon pKa (Strongest Basic) -3 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 99.1 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 60.01 m3·mol-1 Chemaxon Polarizability 24.93 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0006-2900000000-09b1e6a59b50fa1e61b3 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0ap1-1390000000-14471cbe12e293fbd2a4 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00dj-5900000000-ddc80133a4cb0a866a3b Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-006x-9700000000-b3f5f3267c0d99c15612 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-05fr-2900000000-16b4c30ef331da7f8ab5 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-00el-3900000000-c700886627a769a55283 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 169.4208173 predictedDarkChem Lite v0.1.0 [M-H]- 157.09227 predictedDeepCCS 1.0 (2019) [M+H]+ 170.6659173 predictedDarkChem Lite v0.1.0 [M+H]+ 159.48813 predictedDeepCCS 1.0 (2019) [M+Na]+ 169.4463173 predictedDarkChem Lite v0.1.0 [M+Na]+ 165.43129 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Cell-cycle-regulated enzyme of importance in nucleotide metabolism (PubMed:9575153). Catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate (PubMed:22385435). Transcriptional regulation limits expression to the S phase of the cell cycle and transient expression coincides with the oscillation in the intracellular dTTP concentration (Probable). Also important for the activation of anticancer and antiviral nucleoside analog prodrugs such as 1-b-d-arabinofuranosylcytosine (AraC) and 3c-azido-3c-deoxythymidine (AZT) (PubMed:22385435).
- Specific Function
- ATP binding
- Gene Name
- TK1
- Uniprot ID
- P04183
- Uniprot Name
- Thymidine kinase, cytosolic
- Molecular Weight
- 25468.455 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Human herpesvirus 1
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Replicates viral genomic DNA. The replication complex is composed of six viral proteins: the DNA polymerase, processivity factor, primase, primase-associated factor, helicase, and ssDNA-binding protein. Additionally, the polymerase contains an intrinsic ribonuclease H (RNase H) activity that specifically degrades RNA/DNA heteroduplexes or duplex DNA substrates in the 5' to 3' direction. Therefore, it can catalyze the excision of the RNA primers that initiate the synthesis of Okazaki fragments at a replication fork during viral DNA replication.
- Specific Function
- 3'-5'-DNA exonuclease activity
- Gene Name
- DNApol
- Uniprot ID
- Q91CQ6
- Uniprot Name
- DNA polymerase
- Molecular Weight
- 136474.73 Da
References
- National Cancer Institute [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017).
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- 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. [Article]
Drug created at June 23, 2017 20:41 / Updated at August 26, 2024 19:22