2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis

• Published in: Journal of medicinal chemistry 2006-03, Vol.49 (5), p.1693-1705
• Main Authors: Koch, Uwe, Attenni, Barbara, Malancona, Savina, Colarusso, Stefania, Conte, Immacolata, Di Filippo, Marcello, Harper, Steven, Pacini, Barbara, Giomini, Claudia, Thomas, Steven, Incitti, Ilario, Tomei, Licia, De Francesco, Raffaele, Altamura, Sergio, Matassa, Victor G, Narjes, Frank
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; Cell Line; Chelating Agents - chemistry; Crystallization; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepatitis C virus; Humans; Methylurea Compounds - chemical synthesis; Methylurea Compounds - chemistry; Methylurea Compounds - pharmacology; Models, Molecular; Mutagenesis; Protein Conformation; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051064t

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 μM), which now show activity in the cell-based HCV replication assay. The structure−activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.