 |
|
|
| |
GSK625433: A Novel and Highly potent Inhibitor of the HCV NS5B Polymerase
|
| |
| |
Reported by Jules Levin
EASL April 11-15, 2007 (European liver meeting)
Barcelona
F Gray et al. Infectipus Disease Center for Excellence in Drug Discovery, Stevenage, UK
The HCVNs5B gene encodes the viral RNA dependent RNA polymerase (RdRP) which is essential for HCV replication. The HCV polymerase has multiple inhibitor binding sites making it an attractive target for antiviral therapy. We report the discovery of a novel and potent HCV polymerase inhibitor, GSK625433, an acylpyrrolidine (AP) with good pharmacokinetic profile in pre-clinical animal species and complementary resistance pattern to other HCV clinical candidates.
The AP series of NS5B inhibitors was optimized through parallel use of enzyme and cell-based assays and by monitoring PK parameters of key compounds in the rat, to deliver GSK625433 as a molecule suitable for clinical evaluation. In vitro activity was measured in both isolated NS5B enzyme assays and HCV replicons of genotypes 1a and 1b. Resistant replicons were selected by treating replicon cells with GSK625433 and individual mutations assessed in enzyme and transient replicon assays. Selectivity was measured against human cellular DNA polymerases and cytotoxicity determined in Vero and Huh cell lines.
GSK625433 is a highly potent and selective inhibitor of the HCV genotype 1a and 1b NS5B polymerases (<100nM). In the HCV replicon system, the EC50 of GSK625433 is 2nM against 1b and 290nM against 1a. The compound exhibits synergy with interferon alpha in the replicon system and activity is not significantly attenuated in presence of human strum. GSK625433 does not inhibit human cellular DNA polymerases and shows an excellent cytotoxicity window in relevant cells. Structural alalyses reveal that the APs bind in the palm region of NS5B near the active site of the polymerase. Consistent with the structural analyses, resistance studies have identified M414T and I447F as the key mutations in the palm region conferring resistance to GSK625433. The compound remains active against HCV replicons and enzymes resistant to other classes of polymerase inhibitor. GSK625433 has good bioavailability in both rat and dog.
In conclusion, GSK625433 is a highly potent and selective inhibitor of HCV NS5B polymerase. Its profile supports progression to clinical evaluation in HCV infected patients in combination with current therapies and as part of new combination antiviral regimen.
|
| |
|
|
|
|
|
