N4-Hydroxycytidine

Identification

Name
N4-Hydroxycytidine
Accession Number
DB15660
Description

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
Thumb
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

Contraindications & Blackbox Warnings
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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
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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

Affected organisms
  • Influenza Virus
  • SARS-CoV
  • SARS-CoV-2
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.

Products

Categories

Drug Categories
Classification
Not classified

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

References

General References
  1. 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. [PubMed:29167335]
  2. 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. [PubMed:31494195]
  3. 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..
  4. 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. [PubMed:16723558]
  5. 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. [PubMed:7366595]
  6. 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. [PubMed:31645453]
  7. Hampton T: New Flu Antiviral Candidate May Thwart Drug Resistance. JAMA. 2020 Jan 7;323(1):17. doi: 10.1001/jama.2019.20225. [PubMed:31910262]
ChemSpider
170635
ChEMBL
CHEMBL2178720

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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
PropertyValueSource
Water Solubility34.4 mg/mLALOGPS
logP-2ALOGPS
logP-2.7ChemAxon
logS-0.88ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)2.39ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area134.85 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity66.8 m3·mol-1ChemAxon
Polarizability23.55 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
Not Available

Drug created on April 06, 2020 19:58 / Updated on June 12, 2020 10:53

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