Optimization and SAR research at the benzoxazole and tetrazole rings of JNJ4796 as new anti-influenza A virus agents, part 2.
Eur J Med Chem
; 245(Pt 1): 114906, 2023 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-36395647
ABSTRACT
We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.
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Base de dados:
MEDLINE
Assunto principal:
Antivirais
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Piperazinas
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Tetrazóis
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Benzoxazóis
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Vírus da Influenza A Subtipo H1N1
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article