Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase

Cliff C Cheng; Xiaohua Huang; Gerald W Shipps Jr; Yu-Sen Wang; Daniel F Wyss; Kyle A Soucy; Chuan-Kui Jiang; Sony Agrawal; Eric Ferrari; Zhiqing He; H-C Huang

doi:10.1021/ml100128h

Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase

ACS Med Chem Lett. 2010 Aug 17;1(9):466-71. doi: 10.1021/ml100128h. eCollection 2010 Dec 9.

Authors

Affiliations

¹ Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
² Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.

Abstract

Pyridine carboxamide-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified and optimized to a variety of topologically related scaffolds. In particular, the 2-methyl nicotinic acid scaffold was developed into inhibitors with improved biochemical (IC50-GT1b = 0.014 μM) and cell-based HCV replicon potency (EC50-GT1b = 0.7 μM). Biophysical and biochemical characterization identified this novel series of compounds as palm site binders to HCV polymerase.

Keywords: 2D 15N-HSQC; HCV NS5B polymerase; Hepatitis C virus; automated ligand identification system (ALIS); direct-acting antiviral (DAA); palm site inhibitors.