Studies on acyl pyrrolidine inhibitors of HCV RNA-dependent RNA polymerase to identify a molecule with replicon antiviral activity

The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta 21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon). (c) 2007 Elsevier Ltd. All rights reserved.

Identification of GSK625433: A novel clinical candidate for the treatment of hepatitis C.

Hepatitis C is an infection of the liver caused by a pos. single-stranded RNA virus (HCV) which affects 170 million people worldwide. It is responsible for 40-60% of all liver disease and is the major cause of liver transplants in the United States. The HCV NS5B gene encodes the viral RNA-dependent RNA polymerase which is essential for HCV replication. We have previously reported the identification of acylpyrrolidines as potent inhibitors of NS5B; however their activity is attenuated against genotype 1a. The design of improved broader-spectrum compds., capable of effective inhibition of both genotypes 1b and 1a is desirable. An understanding of the binding site and genotype sequence differences was utilized to design compds. with greatly enhanced genotype 1a and 1b potency. Our studies led to the identification of GSK625433, a potent, homochiral inhibitor of these HCV genotypes in both enzyme and sub-genomic replicon cell-based assays. GSK625433 has a good pharmacokinetic profile in pre-clin. animal species, enabling progression to clin. evaluation.

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.