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
- 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][[email protected]@]12COCCN1C(=O)C1=C(OCOC(=O)OC)C(=O)C=CN1N2[[email protected]]1C2=CC=C(F)C(F)=C2CSC2=CC=CC=C12
Pharmacology
- Indication
- Structured Indications
- Not Available
- 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 [L14785].
- 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
References
- General References
- NME submissions and their additional indications Projects currently in phase II and III [Link]
- 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]
- Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor [Link]
- A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase [Link]
- Pharmacokinetics/pharmacodynamics of S-033188 [Link]
- 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]
- ABC News- Xofluza [Link]
- External Links
- KEGG Drug
- D11021
- ChemSpider
- 59718643
- Wikipedia
- Baloxavir_marboxil
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Flu caused by Influenza 1 3 Recruiting Treatment Flu caused by Influenza 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Soluble in DSMO https://medkoo.com/products/12071 - Predicted Properties
Property Value Source Water Solubility 0.0412 mg/mL ALOGPS logP 2.12 ALOGPS logP 3.38 ChemAxon logS -4.1 ALOGPS pKa (Strongest Basic) -0.6 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 8 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 97.85 Å2 ChemAxon Rotatable Bond Count 6 ChemAxon Refractivity 140.76 m3·mol-1 ChemAxon Polarizability 53.87 Å3 ChemAxon Number of Rings 6 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - 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 March 02, 2018 04:34