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

• 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: Acid replacements; Allosteric inhibition; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Carboxylic Acids - chemistry; Cell Line; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hepatitis C virus; Humans; Indoleacetic Acids - chemistry; Indoleacetic Acids - pharmacology; Indoles; Medical sciences; NS5B polymerase; Pharmacology. Drug treatments; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.093

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.