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Identification
NameZanamivir
Accession NumberDB00558  (APRD00378)
TypeSmall Molecule
GroupsApproved, Investigational
Description

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

Structure
Thumb
Synonyms
SynonymLanguageCode
(2R,3R,4S)-3-(acetylamino)-4-Carbamimidamido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acidNot AvailableNot Available
4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acidNot AvailableNot Available
4-Guanidino-neu5ac2enNot AvailableNot Available
5-(acetylamino)-2,6-Anhydro-4-carbamimidamido-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acidNot AvailableNot Available
5-acetamido-2,6-Anhydro-3,4,5-trideoxy-4-guanidino-D-glycero-D-galacto-non-2-enonic acidNot AvailableNot Available
GANANot AvailableNot Available
GNANot AvailableNot Available
Modified sialic acidNot AvailableNot Available
RelenzaNot AvailableNot Available
ZanamavirNot AvailableNot Available
ZANAMIVIRNot AvailableNot Available
ZMRNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
RelenzaGlaxoSmithKline
Brand mixturesNot Available
Categories
CAS number139110-80-8
WeightAverage: 332.3098
Monoisotopic: 332.133199014
Chemical FormulaC12H20N4O7
InChI KeyARAIBEBZBOPLMB-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
[H][C@]1(OC(=C[C@H](N=C(N)N)[C@H]1NC(C)=O)C(O)=O)[C@H](O)[C@H](O)CO
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassSugar Acids and Derivatives
Direct parentPyranoid Amino Acids and Derivatives
Alternative parentsPyran Carboxylic Acids and Derivatives; Secondary Alcohols; Secondary Carboxylic Acid Amides; Guanidines; 1,2-Diols; Primary Alcohols; Enolates; Carboxylic Acids; Amidines; Polyamines
Substituentspyran carboxylic acid; secondary carboxylic acid amide; guanidine; 1,2-diol; secondary alcohol; polyol; carboxamide group; amidine; polyamine; enolate; primary alcohol; carboxylic acid derivative; carboxylic acid; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the pyranoid amino acids and derivatives. These are compounds containing a (hydro)pyran ring bearing unprotected amino and carboxylic acid functionalities.
Pharmacology
IndicationFor the prevention and treatment of influenza A and B.
PharmacodynamicsZanamivir, 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 actionThe 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.
AbsorptionAbsolute bioavailability is very low following oral administration (2%). Following oral inhalation, bioavailability is 4% to 17%.
Volume of distributionNot Available
Protein bindingZanamivir has limited plasma protein binding (<10%).
Metabolism

Not metabolized

Route of eliminationIt 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 life2.5-5.1 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]
ToxicityNot Available
Affected organisms
  • Influenza A virus
  • Influenza B virus
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.8406
Blood Brain Barrier - 0.8899
Caco-2 permeable - 0.7094
P-glycoprotein substrate Substrate 0.5497
P-glycoprotein inhibitor I Non-inhibitor 0.8288
P-glycoprotein inhibitor II Non-inhibitor 0.9701
Renal organic cation transporter Non-inhibitor 0.9405
CYP450 2C9 substrate Non-substrate 0.7868
CYP450 2D6 substrate Non-substrate 0.8139
CYP450 3A4 substrate Non-substrate 0.6779
CYP450 1A2 substrate Non-inhibitor 0.8684
CYP450 2C9 substrate Non-inhibitor 0.8942
CYP450 2D6 substrate Non-inhibitor 0.9262
CYP450 2C19 substrate Non-inhibitor 0.8727
CYP450 3A4 substrate Non-inhibitor 0.9647
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9903
Ames test Non AMES toxic 0.5316
Carcinogenicity Non-carcinogens 0.9226
Biodegradation Ready biodegradable 0.6996
Rat acute toxicity 2.1565 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9827
hERG inhibition (predictor II) Non-inhibitor 0.9528
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
Packagers
Dosage forms
FormRouteStrength
PowderRespiratory (inhalation)
Prices
Unit descriptionCostUnit
Relenza Diskhaler 20 5 mg/blister Aerosol Inhaler75.73USDinhaler
Relenza 5 mg diskhaler3.54USDeach
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States62945721994-12-152014-12-15
United States53608171993-07-262013-07-26
Canada22919942003-10-142011-04-24
Canada20813562000-02-222011-04-24
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP-3Not Available
Predicted Properties
PropertyValueSource
Water Solubility7.31ALOGPS
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
Spectra
SpectraNot 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 Reference
  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
  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
  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 Aug 11. Pubmed
  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. Pubmed
External Links
ResourceLink
KEGG DrugD00902
KEGG CompoundC08095
PubChem Compound60855
PubChem Substance46508581
ChemSpider54842
BindingDB4934
ChEBI50663
ChEMBLCHEMBL222813
Therapeutic Targets DatabaseDAP000715
PharmGKBPA164740891
HETZMR
Drug Product Database2240863
RxListhttp://www.rxlist.com/cgi/generic2/zanam.htm
Drugs.comhttp://www.drugs.com/cdi/zanamivir.html
WikipediaZanamivir
ATC CodesJ05AH01
AHFS Codes
  • 08:18.28
PDB Entries
FDA labelshow(36.7 KB)
MSDSshow(53.6 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Neuraminidase

Kind: protein

Organism: Influenza A virus (strain A/Bangkok/1/1979 H3N2)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Neuraminidase P06818 Details

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
  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
  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
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Neuraminidase

Kind: protein

Organism: Influenza B virus (strain B/Beijing/1/1987)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Neuraminidase P27907 Details

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
  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 Aug 9. Pubmed

3. Sialidase-2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Sialidase-2 Q9Y3R4 Details

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. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11