Evaluation of the anti-hepatitis C virus effect of novel potent, selective, and orally bioavailable JNK and VEGFR kinase inhibitors.
Bioorg Med Chem Lett
; 17(7): 1843-9, 2007 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-17289388
ABSTRACT
Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC(50) of 64nM, associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. Moreover, 36 showed an advantageous PK profile in mice. Experiments performed using different replicon constructs suggest that this series of kinase inhibitors might mediate their effect through the HCV non-structural protein 5A (NS5A).
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Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Química Farmacêutica
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Proteínas não Estruturais Virais
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Hepacivirus
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Receptor 1 de Fatores de Crescimento do Endotélio Vascular
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MAP Quinase Quinase 4
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Inibidores Enzimáticos
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article