Evaluation of the anti-influenza virus activities of 1,3,4-thiadiazol-2-ylcyanamide (LY217896) and its sodium salt.
1,3,4-Thiadiazol-2-ylcyanamide (LY217896) and its sodium salt were shown to be effective against influenza A and B viruses in vitro and in the mouse model. In nondividing confluent MDCK cells, the 50% inhibitory concentration of LY217896 ranged from 0.37 to 1.19 micrograms/ml against various strains of influenza A virus and from 0.75 to 1.54 micrograms/ml against various strains of influenza B virus, with no apparent cytotoxicity. However, at a concentration of 0.31 microgram/ml, LY217896 inhibited the replication of dividing MDCK cells. LY217896 (9 mg/m2 of body surface area per day) administered in the diet, in the drinking water, by oral gavage, by intraperitoneal injection, or by aerosolization was well tolerated and protected CD-1 mice infected with a lethal dose of influenza A or B virus. Effective administration of the compound could be delayed for up to 96 h postinfection. Virus titer was reduced by 1 to 2 log10 units in lungs of mice given LY217896 in the drinking water. Mice treated initially with protective levels of LY217896 were resistant to a subsequent challenge of influenza virus in the absence of the compound, indicating that the animals were able to develop immunity to the initial infection. Administration of LY217896 to uninfected mice did not induce interferon-like activity or interfere with natural killer cell function. In the ferret, LY217896 was effective in preventing fever induced by influenza virus.
Colacino
J M
JM
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285.
DeLong
D C
DC
Nelson
J R
JR
Spitzer
W A
WA
Tang
J
J
Victor
F
F
Wu
C Y
CY
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D005289:Ferrets; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000382:microbiology; D007369:Interferon Inducers; D007694:Killer Cells, Natural / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D009975:Orthomyxoviridae / Q000187:drug effects*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D007369:Interferon Inducers; D009570:Nitriles; D013830:Thiadiazoles; C067593:1,3,4-thiadiazol-2-ylcyanamide