title: 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.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Inna
authors.initials: I
authors.lastname: Karpenko
authors.forename: Sergey
authors.initials: S
authors.lastname: Deev
authors.forename: Oleg
authors.initials: O
authors.lastname: Kiselev
authors.forename: Valerey
authors.initials: V
authors.lastname: Charushin
authors.forename: Vladimir
authors.initials: V
authors.lastname: Rusinov
authors.forename: Eugeney
authors.initials: E
authors.lastname: Ulomsky
authors.forename: Ella
authors.initials: E
authors.lastname: Deeva
authors.forename: Dmitry
authors.initials: D
authors.lastname: Yanvarev
authors.forename: Alexander
authors.initials: A
authors.lastname: Ivanov
authors.forename: Olga
authors.initials: O
authors.lastname: Smirnova
authors.forename: Sergey
authors.initials: S
authors.lastname: Kochetkov
authors.forename: Oleg
authors.initials: O
authors.lastname: Chupakhin
authors.forename: Marina
authors.initials: M
authors.lastname: Kukhanova
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001393:Azoles / Q000737:chemistry / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D015195:Drug Design; D022781:Hepatocytes / Q000166:cytology / Q000821:virology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development; D009981:Influenza B virus / Q000187:drug effects* / Q000254:growth & development; D007275:Injections, Intravenous; D007668:Kidney / Q000166:cytology; D051379:Mice; D008808:Mice, Inbred CBA; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D011817:Rabbits; D013270:Stomach; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics*; D014230:Triazoles; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001393:Azoles; D014227:Triazines; D014230:Triazoles; C539416:riamilovir