Inhibitors of hepatitis C virus NS3·4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics

Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3·4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3·4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.

A series of tetrapeptide HCV NS34A protease inhibitors with varying P4 capping groups were prepared. The SAR and pharmacokinetic properties of these inhibitors are discussed.Figure optionsDownload as PowerPoint slide