Inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

Abstract

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 diketoacids 1 and dihydroxypyrimidine carboxylates 3 as novel, reversible inhibitors of the HCV NS5B polymerase. We report here the further development of 3 into the more potent 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids. The structure activity relationship of these inhibitors is discussed in the context of their physicochemical properties, supporting the proposed binding model, which involves pyrophosphate like chelation of the active site Mg-ions. We also report on the discovery and synthesis of two related scaffolds, the N1-substituted pyrimidones and pyridine-N-oxides.