Identification

Name
Zanamivir
Accession Number
DB00558  (APRD00378)
Type
Small Molecule
Groups
Approved, Investigational
Description

A guanido-neuraminic acid that is used to inhibit neuraminidase. [PubChem]

Structure
Thumb
Synonyms
  • (2R,3R,4S)-3-(acetylamino)-4-Carbamimidamido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid
  • 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid
  • 4-Guanidino-neu5ac2en
  • 5-(acetylamino)-2,6-Anhydro-4-carbamimidamido-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid
  • 5-acetamido-2,6-Anhydro-3,4,5-trideoxy-4-guanidino-D-glycero-D-galacto-non-2-enonic acid
  • GANA
  • GNA
  • Modified sialic acid
  • Zanamavir
  • ZANAMIVIR
  • ZMR
External IDs
GG-167 / GR-121167X
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RelenzaPowder5 mg/1Respiratory (inhalation)Physicians Total Care, Inc.2009-01-20Not applicableUs
RelenzaPowder5 mg/1Respiratory (inhalation)Glaxosmithkline Inc1999-09-22Not applicableUs
RelenzaPowder5 mg/1Respiratory (inhalation)Dispensing Solutions, Inc.2002-12-22Not applicableUs
RelenzaPowder5 mgOral; Respiratory (inhalation)Glaxosmithkline Inc1999-12-07Not applicableCanada
International/Other Brands
Relenza
Categories
UNII
L6O3XI777I
CAS number
139110-80-8
Weight
Average: 332.3098
Monoisotopic: 332.133199014
Chemical Formula
C12H20N4O7
InChI Key
ARAIBEBZBOPLMB-UFGQHTETSA-N
InChI
InChI=1S/C12H20N4O7/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16)/t5-,6+,8+,9+,10+/m0/s1
IUPAC Name
(2R,3R,4S)-4-[(diaminomethylidene)amino]-3-acetamido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid
SMILES

Pharmacology

Indication

For the prevention and treatment of influenza A and B.

Structured Indications
Pharmacodynamics

Zanamivir, an antiviral agent, is a neuraminidase inhibitor indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients 7 years and older who have been symptomatic for no more than 2 days. Zanamivir has also been shown to significantly inhibit the human sialidases NEU3 and NEU2 in the micromolar range (Ki 3.7 +/-0.48 and 12.9+/-0.07 microM, respectively), which could account for some of the rare side effects of zanamivir.

Mechanism of action

The proposed mechanism of action of zanamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. By binding and inhibiting the neuraminidase protein, the drug renders the influenza virus unable to escape its host cell and infect others.

TargetActionsOrganism
ANeuraminidase
inhibitor
Influenza A virus (strain A/Bangkok/1/1979 H3N2)
ANeuraminidase
inhibitor
Influenza B virus (strain B/Beijing/1/1987)
USialidase-2
inhibitor
Human
Absorption

Absolute bioavailability is very low following oral administration (2%). Following oral inhalation, bioavailability is 4% to 17%.

Volume of distribution
Not Available
Protein binding

Zanamivir has limited plasma protein binding (<10%).

Metabolism

Not metabolized

Route of elimination

It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Unabsorbed drug is excreted in the feces.Zanamivir is renally excreted as unchanged drug.

Half life

2.5-5.1 hours

Clearance
  • 2.5 - 10.9 L/h [Following oral inhalation 10 mg]
  • 5.3 L/h [Normal renal function receiving IV single dose of 4 mg or 2 mg]
  • 2.7 L/h [Patients with mild and moderate renal impairement receiving IV single dose of 4 mg or 2 mg]
  • 0.8 L/h [Patients with severe renal impairement receiving IV single dose of 4 mg or 2 mg]
Toxicity
Not Available
Affected organisms
  • Influenza A virus
  • Influenza B virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference

Manjinder Singh Phull, Rajendra Narayanrao Kankan, Dharmaraj Ramachandra Rao, Ashwini Amol Sawant, Sanoj Thoppil, "Process for Preparing Zanamivir and Intermediates for Use in the Process." U.S. Patent US20110257418, issued October 20, 2011.

US20110257418
General References
  1. Meindl P, Bodo G, Palese P, Schulman J, Tuppy H: Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology. 1974 Apr;58(2):457-63. [PubMed:4362431]
  2. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW, et al.: Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature. 1993 Jun 3;363(6428):418-23. [PubMed:8502295]
  3. Hata K, Koseki K, Yamaguchi K, Moriya S, Suzuki Y, Yingsakmongkon S, Hirai G, Sodeoka M, von Itzstein M, Miyagi T: Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob Agents Chemother. 2008 Oct;52(10):3484-91. doi: 10.1128/AAC.00344-08. Epub 2008 Aug 11. [PubMed:18694948]
  4. Sugaya N, Tamura D, Yamazaki M, Ichikawa M, Kawakami C, Kawaoka Y, Mitamura K: Comparison of the clinical effectiveness of oseltamivir and zanamivir against influenza virus infection in children. Clin Infect Dis. 2008 Aug 1;47(3):339-45. doi: 10.1086/589748. [PubMed:18582202]
External Links
Human Metabolome Database
HMDB14698
KEGG Drug
D00902
KEGG Compound
C08095
PubChem Compound
60855
PubChem Substance
46508581
ChemSpider
54842
BindingDB
50330326
ChEBI
50663
ChEMBL
CHEMBL222813
Therapeutic Targets Database
DAP000715
PharmGKB
PA164740891
HET
ZMR
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Zanamivir
ATC Codes
J05AH01 — Zanamivir
AHFS Codes
  • 08:18.28 — Neuraminidase Inhibitors
PDB Entries
1a4g / 1nnc / 1v3e / 2cml / 2f0z / 2htq / 2ya7 / 3b7e / 3ckz / 3san
show 11 more
FDA label
Download (36.7 KB)
MSDS
Download (53.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherInfluenza A Virus, H1N1 Subtype / Influenza, Human1
1CompletedTreatmentFlu caused by Influenza / Virus Diseases1
1CompletedTreatmentInfluenza, Human1
1, 2CompletedTreatmentFlu caused by Influenza1
2TerminatedTreatmentInfluenza A Infection1
3CompletedPreventionFlu caused by Influenza1
3CompletedTreatmentInfluenza A Virus Infection / Influenza B Virus Infection1
3CompletedTreatmentInfluenza, Human1
3TerminatedTreatmentFlu caused by Influenza / Upper Respiratory Tract Infections1
3TerminatedTreatmentGastric Influenza1
4CompletedPreventionFlu caused by Influenza1
Not AvailableCompletedNot AvailableInfluenza, Human1

Pharmacoeconomics

Manufacturers
  • Glaxosmithkline
Packagers
Dosage forms
FormRouteStrength
PowderOral; Respiratory (inhalation)5 mg
PowderRespiratory (inhalation)5 mg/1
Prices
Unit descriptionCostUnit
Relenza Diskhaler 20 5 mg/blister Aerosol Inhaler75.73USD inhaler
Relenza 5 mg diskhaler3.54USD each
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6294572No1994-12-152014-12-15Us
US5360817No1993-07-262013-07-26Us
CA2291994No2003-10-142011-04-24Canada
CA2081356No2000-02-222011-04-24Canada

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP-3Not Available
Predicted Properties
PropertyValueSource
Water Solubility7.31 mg/mLALOGPS
logP-2.3ALOGPS
logP-5.8ChemAxon
logS-1.7ALOGPS
pKa (Strongest Acidic)3.25ChemAxon
pKa (Strongest Basic)11.93ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area200.72 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity76.19 m3·mol-1ChemAxon
Polarizability31.24 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.8406
Blood Brain Barrier-0.8899
Caco-2 permeable-0.7094
P-glycoprotein substrateSubstrate0.5497
P-glycoprotein inhibitor INon-inhibitor0.8288
P-glycoprotein inhibitor IINon-inhibitor0.9701
Renal organic cation transporterNon-inhibitor0.9405
CYP450 2C9 substrateNon-substrate0.7868
CYP450 2D6 substrateNon-substrate0.8139
CYP450 3A4 substrateNon-substrate0.6779
CYP450 1A2 substrateNon-inhibitor0.8684
CYP450 2C9 inhibitorNon-inhibitor0.8942
CYP450 2D6 inhibitorNon-inhibitor0.9262
CYP450 2C19 inhibitorNon-inhibitor0.8727
CYP450 3A4 inhibitorNon-inhibitor0.9647
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9903
Ames testNon AMES toxic0.5316
CarcinogenicityNon-carcinogens0.9226
BiodegradationReady biodegradable0.6996
Rat acute toxicity2.1565 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9827
hERG inhibition (predictor II)Non-inhibitor0.9528
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 acetamides. These are organic compounds with the general formula RNHC(=O)CH3, where R= organyl group.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Carboxylic acid derivatives
Direct Parent
Acetamides
Alternative Parents
Secondary carboxylic acid amides / Secondary alcohols / Guanidines / Propargyl-type 1,3-dipolar organic compounds / Polyols / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Carboximidamides / Primary alcohols
show 4 more
Substituents
Acetamide / Guanidine / Secondary alcohol / Secondary carboxylic acid amide / Carboxylic acid / Oxacycle / Monocarboxylic acid or derivatives / Organoheterocyclic compound / Organic 1,3-dipolar compound / Propargyl-type 1,3-dipolar organic compound
show 13 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
guanidines (CHEBI:50663)

Targets

Kind
Protein
Organism
Influenza A virus (strain A/Bangkok/1/1979 H3N2)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus...
Gene Name
NA
Uniprot ID
P06818
Uniprot Name
Neuraminidase
Molecular Weight
52140.54 Da
References
  1. Macdonald SJ, Cameron R, Demaine DA, Fenton RJ, Foster G, Gower D, Hamblin JN, Hamilton S, Hart GJ, Hill AP, Inglis GG, Jin B, Jones HT, McConnell DB, McKimm-Breschkin J, Mills G, Nguyen V, Owens IJ, Parry N, Shanahan SE, Smith D, Watson KG, Wu WY, Tucker SP: Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. J Med Chem. 2005 Apr 21;48(8):2964-71. [PubMed:15828835]
  2. Murrell MT, Porotto M, Greengard O, Poltoratskaia N, Moscona A: A single amino acid alteration in the human parainfluenza virus type 3 hemagglutinin-neuraminidase glycoprotein confers resistance to the inhibitory effects of zanamivir on receptor binding and neuraminidase activity. J Virol. 2001 Jul;75(14):6310-20. [PubMed:11413297]
  3. Mungall BA, Xu X, Klimov A: Assaying susceptibility of avian and other influenza A viruses to zanamivir: comparison of fluorescent and chemiluminescent neuraminidase assays. Avian Dis. 2003;47(3 Suppl):1141-4. [PubMed:14575130]
  4. 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
Influenza B virus (strain B/Beijing/1/1987)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus...
Gene Name
NA
Uniprot ID
P27907
Uniprot Name
Neuraminidase
Molecular Weight
51429.21 Da
References
  1. Eiland LS, Eiland EH: Zanamivir for the prevention of influenza in adults and children age 5 years and older. Ther Clin Risk Manag. 2007 Jun;3(3):461-5. [PubMed:18488077]
  2. Oakley AJ, Barrett S, Peat TS, Newman J, Streltsov VA, Waddington L, Saito T, Tashiro M, McKimm-Breschkin JL: Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses. J Med Chem. 2010 Sep 9;53(17):6421-31. doi: 10.1021/jm100621s. [PubMed:20695427]
Details
3. Sialidase-2
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Exo-alpha-(2->8)-sialidase activity
Specific Function
Catalyzes the removal of sialic acid (N-acetylneuraminic acid) moities from glycoproteins, oligosaccharides and gangliosides.
Gene Name
NEU2
Uniprot ID
Q9Y3R4
Uniprot Name
Sialidase-2
Molecular Weight
42253.345 Da
References
  1. Chavas LM, Kato R, Suzuki N, von Itzstein M, Mann MC, Thomson RJ, Dyason JC, McKimm-Breschkin J, Fusi P, Tringali C, Venerando B, Tettamanti G, Monti E, Wakatsuki S: Complexity in influenza virus targeted drug design: interaction with human sialidases. J Med Chem. 2010 Apr 8;53(7):2998-3002. doi: 10.1021/jm100078r. [PubMed:20222714]

Drug created on June 13, 2005 07:24 / Updated on October 23, 2017 14:13