P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.
Bioorg Med Chem Lett
; 14(1): 257-61, 2004 Jan 05.
Article
en En
| MEDLINE
| ID: mdl-14684338
With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50mg/kg, 3a achieved 2.5x higher liver and plasma exposure in comparison to that detected with 1a.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Prolina
/
Serina Endopeptidasas
/
Inhibidores de Serina Proteinasa
/
Proteínas no Estructurales Virales
/
Hepacivirus
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2004
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido