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

  • Bioorg Med Chem Lett. 2007 Jun 15;17(12):3406-11. doi: 10.1016/j.bmcl.2007.03.090.
Robert B Perni  1 ,  Gurudatt Chandorkar ,  Kevin M Cottrell ,  Cynthia A Gates ,  Chao Lin ,  Kai Lin ,  Yu-Ping Luong ,  John P Maxwell ,  Mark A Murcko ,  Janos Pitlik ,  Govinda Rao ,  Wayne C Schairer ,  John Van Drie ,  Yunyi Wei
Affiliations
  • 1. Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. [email protected]
PMID: 17482818 DOI: 10.1016/j.bmcl.2007.03.090
Abstract

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.