Abstract
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.
MeSH terms
-
Animals
-
Bridged Bicyclo Compounds / chemistry
-
Cell Line, Tumor
-
Hepacivirus / drug effects*
-
Hepacivirus / enzymology*
-
Humans
-
Liver / drug effects
-
Liver / enzymology
-
Liver / virology
-
Male
-
Proline / chemistry*
-
Proline / pharmacology
-
Rats
-
Rats, Inbred F344
-
Rats, Sprague-Dawley
-
Serine Endopeptidases / metabolism*
-
Serine Proteinase Inhibitors / chemical synthesis*
-
Serine Proteinase Inhibitors / pharmacology
-
Viral Nonstructural Proteins / metabolism*
Substances
-
Bridged Bicyclo Compounds
-
NS3 protein, hepatitis C virus
-
Serine Proteinase Inhibitors
-
Viral Nonstructural Proteins
-
Proline
-
Serine Endopeptidases