Antiviral properties, metabolism, and pharmacokinetics of a novel azolo-1,2,4-triazine-derived inhibitor of influenza A and B virus replication.

Abstract

Influenza viruses of types A and B cause periodic pandemics in the human population. The antiviral drugs approved to combat influenza virus infections are currently limited. We have investigated an effective novel inhibitor of human influenza A and B viruses, triazavirine [2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4I)-one] (TZV). TZV suppressed the replication of influenza virus in cell culture and in chicken chorioallantoic membranes, and it protected mice from death caused by type A and B influenza viruses. TZV was also effective against a rimantadine-resistant influenza virus strain and against avian influenza A virus H5N1 strains. The pharmacokinetic parameters and bioavailability of TZV were calculated after the administration of TZV to rabbits. The TZV metabolite AMTZV [2-methylthio-6-amino-1,2,4-triazolo[5,1-s]-1,2,4-triazin(e)-7(4I)-one] was discovered in IAK 293T and Huh7 cell cultures, a liver homogenate, and rabbit blood after intragastric administration of TZV. AMTZV was nontoxic and inactive as an inhibitor of influenza virus in cell culture. Most likely, this metabolite is a product of TZV elimination.

• Authors: Inna Karpenko, Sergey Deev, Oleg Kiselev, Valerey Charushin, Vladimir Rusinov, Eugeney Ulomsky, Ella Deeva, Dmitry Yanvarev, Alexander Ivanov, Olga Smirnova, Sergey Kochetkov, Oleg Chupakhin, Marina Kukhanova
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 54 Issue 5 Pg. 2017-22 (May 2010) ISSN: 1098-6596 [Electronic] United States
• PMID: 20194696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Azoles
• Triazines
• Triazoles
• riamilovir

Topics

• Animals
• Antiviral Agents (chemistry, pharmacokinetics)
• Azoles (chemistry, pharmacokinetics)
• Disease Models, Animal
• Dogs
• Drug Design
• Hepatocytes (cytology, virology)
• Humans
• Influenza A virus (drug effects, growth & development)
• Influenza B virus (drug effects, growth & development)
• Injections, Intravenous
• Kidney (cytology)
• Mice
• Mice, Inbred CBA
• Orthomyxoviridae Infections (drug therapy)
• Rabbits
• Stomach
• Triazines (chemistry, pharmacokinetics)
• Triazoles
• Virus Replication (drug effects)