Baloxavir marboxil

Identification

Name
Baloxavir marboxil
Accession Number
DB13997
Type
Small Molecule
Groups
Approved, Investigational
Description

Baloxavir marboxil is a medication developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was approved for use in Japan in February 2018 and is in late phase trials in the United States as of early 2018. Roche, which makes Tamiflu, has acquired the license to sell Xofluza internationally, but it may not be until 2019 that it could be available in the United States [7]. Interestingly, a study has determined that administering Baloxavir marboxil with neuraminidase inhibitors leads to a synergistic effect in influenza treatment [6].

Structure
Thumb
Synonyms
Not Available
External IDs
S-033188/S-033447
International/Other Brands
Xofluza (Shionogi)
Categories
Not Available
UNII
505CXM6OHG
CAS number
1985606-14-1
Weight
Average: 571.55
Monoisotopic: 571.122477593
Chemical Formula
C27H23F2N3O7S
InChI Key
RZVPBGBYGMDSBG-GGAORHGYSA-N
InChI
InChI=1S/C27H23F2N3O7S/c1-36-27(35)39-14-38-25-19(33)8-9-31-24(25)26(34)30-10-11-37-12-21(30)32(31)23-15-6-7-18(28)22(29)17(15)13-40-20-5-3-2-4-16(20)23/h2-9,21,23H,10-14H2,1H3/t21-,23+/m1/s1
IUPAC Name
{[(3R)-2-[(2S)-12,13-difluoro-9-thiatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,11,13-hexaen-2-yl]-9,12-dioxo-5-oxa-1,2,8-triazatricyclo[8.4.0.0^{3,8}]tetradeca-10,13-dien-11-yl]oxy}methyl methyl carbonate
SMILES
[H][C@@]12COCCN1C(=O)C1=C(OCOC(=O)OC)C(=O)C=CN1N2[C@H]1C2=CC=C(F)C(F)=C2CSC2=CC=CC=C12

Pharmacology

Indication

Influenza A and B virus infection [1, 2].

Pharmacodynamics

This medication, also known as S-033188, inhibits an enzyme required for viral replication, thus rapidly treating flu virus infection [2] and alleviating the symptoms associated with infection. A single dose of S-033188 was superior to placebo in relieving influenza symptoms and superior to both oseltamivir and placebo drug in virologic outcomes. The safety profile of S-033188 (Baloxavir marboxil) compared favorably with that of oseltamivir, thus making it a suitable option for treatment of the flu virus, in one single dose [2].

Mechanism of action

This drug is a CAP endonuclease inhibitor [1]. The influenza endonuclease is an essential subdomain of the viral RNA polymerase enzyme. CAP endonuclease processes host pre-mRNAs to serve as primers for viral mRNA and therefore has been a common target for studies of anti-influenza drugs.

Viral gene transcription is primed by short-capped oligonucleotides that are cleaved from host cell pre mRNA by endonuclease activity. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5' end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription.The N-terminal domain of PA subunit (PAN) has been confirmed to accommodate the endonuclease activity residues, which is highly preserved among subtypes of influenza A virus and is able to fold functionally [4]. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5' end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription. The endonuclease domain binds the N-terminal half of PA (PAN) and contains a two-metal (Mn2+) active site that selectively cleaves the pre-mRNA substrate at the 3′ end of a guanine [3].

The administration of a CAP endonuclease inhibitor, such as Baloxavir marboxil, prevents the above process from occurring, exhibiting its action at the beginning of the pathway before CAP endonuclease may exert its action [2].

Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Baloxavir marboxil (S-033188) is a prodrug that is hydrolyzed in vivo to its metabolite, S-033447, the active form that selectively inhibits cap-dependent endonuclease, a key enzyme involved in the initiation of mRNA synthesis of influenza viruses [5].

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Adverse effects of this medication include headache and diahrrea as well as increased ALT and AST (liver transaminases). These adverse effects were found, in one study, to occur at a rate of 1-4%, with higher occurrence in the subgroup receiving 40mg of the drug [5].

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. NME submissions and their additional indications Projects currently in phase II and III [Link]
  2. Cap-dependent Endonuclease Inhibitor S-033188 for the Treatment of Influenza: Results from a Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Study in Otherwise Healthy Adolescents and Adults with Seasonal Influenza [Link]
  3. Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor [Link]
  4. A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase [Link]
  5. Pharmacokinetics/pharmacodynamics of S-033188 [Link]
  6. Synergistic Antiviral Activity of S-033188/S-033447, a Novel Inhibitor of Influenza Virus Cap-Dependent Endonuclease, in Combination with Neuraminidase Inhibitors In Vitro [Link]
  7. ABC News- Xofluza [Link]
External Links
KEGG Drug
D11021
ChemSpider
59718643
Wikipedia
Baloxavir_marboxil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentFlu caused by Influenza2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySoluble in DSMOhttps://medkoo.com/products/12071
Predicted Properties
PropertyValueSource
Water Solubility0.0412 mg/mLALOGPS
logP2.12ALOGPS
logP3.38ChemAxon
logS-4.1ALOGPS
pKa (Strongest Basic)-0.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area97.85 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity140.76 m3·mol-1ChemAxon
Polarizability53.87 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Drug created on February 28, 2018 08:53 / Updated on August 02, 2018 07:01