Development of carboxylic acid replacements in indole- N-acetamide inhibitors of hepatitis C virus NS5B polymerase

Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. Here is described the optimization of potent indole- N-acetamides, bearing physicochemically diverse...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (18), p.5143-5149
Main Authors: Stansfield, Ian, Pompei, Marco, Conte, Immacolata, Ercolani, Caterina, Migliaccio, Giovanni, Jairaj, Mark, Giuliano, Claudio, Rowley, Michael, Narjes, Frank
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. Here is described the optimization of potent indole- N-acetamides, bearing physicochemically diverse replacements for the C6 carboxylic acid, with reduced potential for formation of glucuronide conjugates. Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here 2 series of indole- N-acetamides, bearing physicochemically diverse carboxylic acid replacements, which show potent affinity for the NS5B enzyme with reduced potential for formation of glucuronide conjugates. Preliminary optimization of these series furnished compounds that are potent in the blockade of subgenomic HCV RNA replication in HUH-7 cells.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.06.093