In vitro and in vivo activities of anti-influenza virus compound T-705.
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC(50)s) of 0.013 to 0.48 microg/ml, while it showed no cytotoxicity at concentrations up to 1,000 microg/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitor-resistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC(50)s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 x 10(2) PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.
Furuta
Y
Y
Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama, Japan. YOUSUKE_FURUTA@toyama-chemical.co.jp
Takahashi
K
K
Fukuda
Y
Y
Kuno
M
M
Kamiyama
T
T
Kozaki
K
K
Nomura
N
N
Egawa
H
H
Minami
S
S
Watanabe
Y
Y
Narita
H
H
Shiraki
K
K
D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008168:Lung / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009975:Orthomyxoviridae / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use*; D014780:Viruses / Q000187:drug effects
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir