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

Affiliation

1 Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. rperni@sirtrispharma.com

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.

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