Baloxavir marboxil

Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor for the treatment of influenza A and B virus infections.

Product information

CAS Number: 1985606-14-1

Molecular Weight: 571.55

Formula: C27H23F2N3O7S

Synonym:

S-033188

Xofluza

Chemical Name: ({(12aR)-12-[(11S)-7, 8-difluoro-6, 11-dihydrodibenzo[b, e]thiepin-11-yl]-6, 8-dioxo-3, 4, 6, 8, 12, 12ahexahydro-1H-[1, 4]oxazino[3, 4-c]pyrido[2, 1-f][1, 2, 4]triazin-7-yl}oxy)methyl methyl carbonate

Smiles: COC(=O)OCOC1=C2C(=O)N3CCOC[C@H]3N([C@H]3C4=CC=C(F)C(F)=C4CSC4=CC=CC=C43)N2C=CC1=O

InChiKey: 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

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 50 mg/mL (87.48 mM)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

To evaluate the inhibitory effects of BXA (baloxavir acid, the active form of baloxavir marboxil) against various types of viruses, clinical isolates and animal-derived influenza viruses were subjected to susceptibility testing. BXA exhibited high potency against clinical isolates from influenza A and B viruses with mean EC90 values ranging from 0.63 to 0.95 nM and 6.1–6.5 nM, respectively. When tested with various subtypes of animal influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9, and H9N2), the inhibitory potency of BXA was comparable to the levels seen with H1N1 and H3N2 viruses (Table 3). The mean EC50 values of BXA for these strains of influenza A and B viruses, which included a NAI-resistant strain, ranged from 0.20 to 1.9 nM and 3.3–13 nM, respectively (Table S1). The results suggest that BXA has both potent and broad activity against influenza A and B viruses compared to the other marketed drugs, including strains from laboratory, clinical isolates, and recent vaccine strains. To confirm that BXA targets CEN activity in infected cells, viral mRNA, vRNA and cRNA levels in the presence of BXA were quantified with the A/WSN/33-infected cells. At 5 h post-infection, BXA inhibited viral mRNA, vRNA, and cRNA synthesis in infected cells with mean EC90 values of 13, 13, and 16 nM, respectively (Fig. 3). Intriguingly, BXA achieved 4 log10 reduction in mRNA levels at a lower concentration than favipiravir.The results suggest that BXA blocks viral mRNA, vRNA and cRNA synthesis at the early stage of viral replication in infected cells.

In Vivo:

In this study, the antiviral effects of BXM (baloxavir marboxil) against influenza A virus infection in the ferret model were examined. The maximum virus titer in nasal washes in vehicle‐treated ferrets was detected on Day 2 p.i., followed by a decline by Day 3 p.i. (Figure 3B). BXM at doses of 10 and 30 mg/kg showed a similar reduction in virus titer to an undetectable level (ie, <0.5 log10 TCID50/mL) at Day 2 p.i. The suppression of body temperature changes over time from 8 hours up to Day 3 p.i. was significantly greater with BXM at doses of 10 and 30 mg/kg than vehicle and OSP 5 mg/kg. In the second part of the experiments, ferrets were infected with influenza A/Kadoma/3/2006 (H1N1) strain intranasally at 5000 TCID50/ferret, which was a fivefold higher infectious dose increasing the body temperature by >1° by Day 2 p.i. BXM treatment at Day 2 for 1 day at the dose of 10 mg/kg resulted in a statistically significant reduction in virus titer by Day 3. These results highlight the magnitude and rapidity of the antiviral effects of BXM against influenza A virus infection.

References:

1. Imai M, Yamashita M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Kiso M, Murakami J, Yasuhara A, Takada K, Ito M, Nakajima N, Takahashi K, Lopes TJS, Dutta J, Khan Z, Kriti D, van Bakel H, Tokita A, Hagiwara H, Izumida N, Kuroki H, Nishino T, Wada N, Koga M, Adachi E, Jubishi D, Hasegawa H, Kawaoka Y. Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets. Nat Microbiol. 2019 Nov 25.
2. Yoshino R, Yasuo N, Sekijima M. Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil. Sci Rep. 2019 Nov 25;9(1):17464.
3. Kiso M, Yamayoshi S, Furusawa Y, Imai M, Kawaoka Y. Treatment of Highly Pathogenic H7N9 Virus-Infected Mice with Baloxavir Marboxil. Viruses. 2019 Nov 15;11(11). pii: E1066.

Products are for research use only. Not for human use.