[(Biaryloxy)alkyl]isoxazoles: picornavirus inhibitors.
A series of biphenyl analogs, 6, of 5-[5-(2,6-dichloro-5-oxazolylphenoxy)pentyl]-3-methylisoxazole (2) have been synthesized and tested in vitro against 10 human rhinovirus serotypes in a TCID50 assay. The most potent compound in the series 6s, 3-[3-[2,6-dimethyl-4-(4-fluorophenyl)-phenoxy]propyl]-3-methylisoxazole , was screened against an additional 84 serotypes. It was found to be active against 64 of the serotypes, while 87 serotypes were sensitive to 2 at < 3 micrograms/mL. On comparison of the active serotypes, 6s exhibited greater potency versus 2. Analogs 6a-c,s were examined for in vitro metabolic stability by monkey liver microsomal assay. These analogs exhibited a greater than 7-fold improvement (t1/2 > 200 min) in metabolic stability compared with 2 (t1/2 > 27 min).
Guiles
J W
JW
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426-0900, USA.
Diana
G D
GD
Pevear
D C
DC
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000882:Haplorhini; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010849:Picornaviridae / Q000187:drug effects*
D000998:Antiviral Agents; D007555:Isoxazoles