Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
J Med Chem
; 55(7): 3021-6, 2012 Apr 12.
Article
em En
| MEDLINE
| ID: mdl-22471376
ABSTRACT
The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Ureia
/
Inibidores de Serina Proteinase
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Proteínas não Estruturais Virais
/
Hepacivirus
/
Farmacorresistência Viral
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2012
Tipo de documento:
Article