Synthesis, antiviral activity, and biological properties of vinylacetylene analogs of enviroxime.
A series of vinylacetylene analogs of Enviroxime (1) was synthesized. The new compounds are potent inhibitors of poliovirus in tissue culture. Cross-sensitivity with Enviroxime-derived mutants shows that the new compounds have the same mechanism of action as Enviroxime, which involves the viral 3A protein. In studies with Rhesus monkeys, the p-fluoro derivative 12 was found to be unique in providing oral bioavailability. Metabolism studies using hepatic microsomes suggest that this procedure would be a useful in vitro method for selecting the appropriate animal model for testing oral absorption. Compound 12 was found to be efficacious by oral administration in treating a Coxsackie A21 infection in CD-1 mice.
Victor
F
F
Infectious Diseases Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.
Brown
T J
TJ
Campanale
K
K
Heinz
B A
BA
Shipley
L A
LA
Su
K S
KS
Tang
J
J
Vance
L M
LM
Spitzer
W A
WA
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004770:Enterovirus / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010091:Oximes; D017955:Poliovirus / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides
D000998:Antiviral Agents; D001562:Benzimidazoles; D010091:Oximes; D013449:Sulfonamides; C021595:viroxime