N4-Hydroxycytidine
Explore a selection of our essential drug information below, or:
Identification
- Summary
N4-Hydroxycytidine is a cytidine analog being investigated to treat COVID-19.
- Generic Name
- N4-Hydroxycytidine
- DrugBank Accession Number
- DB15660
- Background
N4-Hydroxyctidine, or EIDD-1931, is a ribonucleoside analog which induces mutations in RNA virions.1,2 N4-hydroxycytidine was first described in the literature in 1980 as a potent mutagen of bacteria and phage.5 It has shown antiviral activity against Venezuelan equine encephalitis virus,1 and the human coronavirus HCoV-NL63 in vitro.4 N4-hydroxycytodine has been shown to inhibit SARS-CoV-2 as well as other human and bat coronaviruses in mice and human airway epithelial cells.3 It is orally bioavailable in mice and distributes into tissue before becoming the active 5’-triphosphate form, which is incorporated into the genome of new virions, resulting in the accumulation of inactivating mutations.2 In non-human primates, N4-hydroxycytidine was poorly orally bioavailable.6 A remdesivir resistant mutant mouse hepatitis virus has also been shown to have increased sensitivity to N4-hydroxycytidine.3 The prodrug of N4-hydroxycytidine, EIDD-2801, is also being investigated for its broad spectrum activity against the coronavirus family of viruses.3
- Type
- Small Molecule
- Groups
- Experimental
- Structure
- Weight
- Average: 259.218
Monoisotopic: 259.080435151 - Chemical Formula
- C9H13N3O6
- Synonyms
- 4-N-Hydroxycytidine
- beta-D-N-4-Hydroxycytidine
- Beta-D-N4-hydroxycytidine
- N(4)-Hydroxycytidine
- NHC
- Uridine, 4-oxime
- β-D-N4-hydroxycytidine
- External IDs
- EIDD-1931
Pharmacology
- Indication
N4-hydroxycytidine and its prodrug EIDD-2801 is being studied for its activity against a number of viral infections including influenza, MERS-CoV, and SARS-CoV-2.3,7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Not Available
- Mechanism of action
N4-hydroxycytidine is phosphorylated in tissue to the active 5’-triphosphate form, which is incorporated into the genome of new virions, resulting in the accumulation of inactivating mutations, known as viral error catastrophe.2,7 A remdesivir resistant mutant mouse hepatitis virus has also been shown to have increased sensitivity to N4-hydroxycytidine.3
- Absorption
N4-hydroxycytidine is orally bioavailable in mice2 but poorly bioavailable in non-human primates.6
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
N4-hydroxycytidine distributes into tissues where it is is phosphorylated to the 5'-triphosphate form.6
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Data regarding overdose of N4-hydroxycytidine is not readily available. The therapeutic index of N4-hydroxycytidine against a clinical isolate of SARS-CoV-2 is expected to be >100, with an in vitro IC50 of 0.3µM and a CC50 of >10µM.3
- 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
- No interactions found.
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Influenza Virus
- SARS-CoV
- SARS-CoV-2
Chemical Identifiers
- UNII
- C3D11PV2O4
- CAS number
- 3258-02-4
- InChI Key
- XCUAIINAJCDIPM-XVFCMESISA-N
- InChI
- InChI=1S/C9H13N3O6/c13-3-4-6(14)7(15)8(18-4)12-2-1-5(11-17)10-9(12)16/h1-2,4,6-8,13-15,17H,3H2,(H,10,11,16)/t4-,6-,7-,8-/m1/s1
- IUPAC Name
- 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-(hydroxyamino)-1,2-dihydropyrimidin-2-one
- SMILES
- OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=CC(NO)=NC1=O
References
- General References
- Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA, Lockwood MA, Natchus MG, Crowley MR, Painter GR, Frolova EI, Frolov I: beta-d-N (4)-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome. J Virol. 2018 Jan 17;92(3). pii: JVI.01965-17. doi: 10.1128/JVI.01965-17. Print 2018 Feb 1. [Article]
- Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, Guthrie DB, Hager M, Kuiper DL, Lockwood MA, Mitchell DG, Natchus MG, Sticher ZM, Kolykhalov AA: The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019 Nov;171:104597. doi: 10.1016/j.antiviral.2019.104597. Epub 2019 Sep 5. [Article]
- T. P. Sheahan et al.: An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. Med.. [Article]
- Pyrc K, Bosch BJ, Berkhout B, Jebbink MF, Dijkman R, Rottier P, van der Hoek L: Inhibition of human coronavirus NL63 infection at early stages of the replication cycle. Antimicrob Agents Chemother. 2006 Jun;50(6):2000-8. doi: 10.1128/AAC.01598-05. [Article]
- Sledziewska E, Janion C: Mutagenic specificity of N4-hydroxycytidine. Mutat Res. 1980 Mar;70(1):11-6. doi: 10.1016/0027-5107(80)90053-6. [Article]
- Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, Plesker R, Barrena AH, Reddy PG, Mitchell DG, Shean RC, Bluemling GR, Kolykhalov AA, Greninger AL, Natchus MG, Painter GR, Plemper RK: Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci Transl Med. 2019 Oct 23;11(515). pii: 11/515/eaax5866. doi: 10.1126/scitranslmed.aax5866. [Article]
- Hampton T: New Flu Antiviral Candidate May Thwart Drug Resistance. JAMA. 2020 Jan 7;323(1):17. doi: 10.1001/jama.2019.20225. [Article]
- External Links
- ChemSpider
- 170635
- ChEMBL
- CHEMBL2178720
- PDBe Ligand
- U56
- PDB Entries
- 8tz5
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 34.4 mg/mL ALOGPS logP -2 ALOGPS logP -2.7 Chemaxon logS -0.88 ALOGPS pKa (Strongest Acidic) 12.55 Chemaxon pKa (Strongest Basic) 2.39 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 5 Chemaxon Polar Surface Area 134.85 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 66.8 m3·mol-1 Chemaxon Polarizability 23.55 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 splash10-004i-0900000000-050d08c164b8ae2b5c35 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0059-9610000000-3675ebb3c47f77f17e79 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-004r-7900000000-9842cf230a178dba73bb Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9400000000-e7ea6dc71962382bef34 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-9600000000-a9a3ba783bdb754d8faa Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-000y-9200000000-d85a12bdb5ed9ed87441 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]- 167.3477353 predictedDarkChem Lite v0.1.0 [M+H]+ 167.7309353 predictedDarkChem Lite v0.1.0 [M+Na]+ 167.4888353 predictedDarkChem Lite v0.1.0
Drug created at April 07, 2020 01:58 / Updated at June 12, 2020 16:53