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. 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.
Stansfield
Ian
I
IRBM (Merck Research Laboratories Rome), Via Pontina Km 30,600, 00040 Pomezia, Rome, Italy. ian_stansfield@merck.com
Pompei
Marco
M
Conte
Immacolata
I
Ercolani
Caterina
C
Migliaccio
Giovanni
G
Jairaj
Mark
M
Giuliano
Claudio
C
Rowley
Michael
M
Narjes
Frank
F
D002264:Carboxylic Acids / Q000737:chemistry*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; D017361:Viral Nonstructural Proteins; C015950:indoleacetamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase