[(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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-07, Vol.38 (14), p.2780-2783
Main Authors: Guiles, Joseph W, Diana, Guy D, Pevear, Daniel C
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemistry
Antiviral Agents - metabolism
Antiviral Agents - pharmacology
Biological and medical sciences
Haplorhini
Isoxazoles - chemistry
Isoxazoles - metabolism
Isoxazoles - pharmacology
Medical sciences
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Pharmacology. Drug treatments
Picornaviridae - drug effects
picornavirus
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00014a029