Baloxavir Marboxil a New Drug against Influenza with Noval Mechanism

Baloxavir Marboxil is a new anti-influenza drug developed by Shionogi Pharmaceutical from Japan and Roche from Switzerland. The drug was first approved for use in Japan in February 2018 and later by the FDA in October for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Baloxavir marboxil is a cap-endonuclease inhibitor, which has a unique mechanism of action to Inhibit the proliferation of influenza virus.

Mechanism

Baloxavir marboxil is a prodrug that enters the body and is hydrolyzed to the active substance baloxavir, which plays an anti-influenza virus activity. Baloxavir is a selective inhibitor of influenza cap-endonuclease, an enzyme required for viral gene transcription and replication, which prevents polymerase function and influenza virus mRNA replication. It has therapeutic activity against both influenza A and B virus infections, even strains resistant to current antiviral drugs. Baloxavir marboxil inhibits an enzyme of viral replication, thus the flu virus infection can be rapidly treated and the symptoms will be alleviated.

Features

• • New antiviral influenza drug

Baloxavir marboxil is the first anti-influenza virus drug with a new mechanism in the past 20 years. Cpmpared with traditional anti-influenza drugs, Baloxavir Marboxil selectively inhibits the CAP-endonuclease of influenza virus, thereby preventing polymerase function and influenza virus mRNA replication.This unique mechanism gives Baloxavir Marboxil a unique advantage against influenza viruses.

• • Excellent activity of anti influenzavirus

Baloxavir marboxil has excellent anti-virus performance against influenza, including influenza A virus (IAV) and influenza B virus (IBV). A single dose of Baloxavir marboxil was shown to be superior to placebo in relieving influenza symptoms and superior to both oseltamivir and placebo drug in virologic outcomes (marked by decreased viral load).

• • Highly effective and long acting drug

Baloxavir marboxil is a prodrug. By oral administration, almost all baloxavir marboxil is converted to the active constituent baloxavir. The tmax of Baloxavir to reach the Cmax in vivo is about 4 hours on average. The average half-life of bacalovirda in vivo is approximately 80 hours, so only one dose is needed for most patients. These make Baloxavir marboxil a highly effective and long acting drug.

Synthesis

The synthesis of Baloxavir marboxil mainly divided into two parts. In each part, a main intermediate is synthesized separately. In the synthesis of intermediate A (1985607-83-7), 7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (intermediate A-2, 1370250-39-7) yields the intermediate A by cyclization and reduction reactions.

The coupling of the intermediate A and intermediate B was carried out under dehydration conditions of 1-propanephosphonic anhydride (T3P) and methanesulfonic acid at 70℃ to obtain protected Baloxavir N-2. Compound N-2 was then reacted with 0.6 equivalents of PhBr and K2CO3. Debenzylation was then carried out using LiCl in CH3CONMe2 to give Baloxavir acid in 94% yield. In the final step, Baloxavir acid was reacted with chloromethyl methyl carbonate in dimethylacetamide in 93% yield to form Baloxavir marboxyl.

Usage and dosage

The Baloxavir Marboxil is used for the treatment of acute uncomplicated influenza in patients (adults and pediatric patients 5 years of age and older) who have been symptomatic for no more than 48 hours. Baloxavir marboxil should be taken as a single dose as soon as possible and within 48 hours of influenza symptom onset for treatment of acute uncomplicated influenza. The specific dose should be adjusted according to the patient’s weight as follow:

• • • 20 kg to less than 80 kg: 40mg
    • At least 80 kg: 80mg

Cautions

Hypersensitivity such as anaphylaxis, angioedema, urticaria, and erythema multiforme may occur or be suspected.

Increased incidence of treatment-emergent resistance in patients less than 5 years of age.

Baloxavir Marboxil has not been shown to prevent serious bacterial infections, which may begin with influenza-like symptoms or may coexist with, or occur as, a complication of influenza.