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.

Graphical abstractA 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 full-size imageDownload as PowerPoint slide