Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase.
Bioorg Med Chem Lett
; 29(24): 126104, 2019 12 15.
Article
em En
| MEDLINE
| ID: mdl-30389294
ABSTRACT
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
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Benzofuranos
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Desenho de Fármacos
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Proteínas não Estruturais Virais
Idioma:
En
Revista:
Bioorg Med Chem Lett
Ano de publicação:
2019
Tipo de documento:
Article