title: Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase.
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.
authors.affiliation: Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
authors.forename: Cliff C
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.affiliation: Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
authors.forename: Yu-Sen
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wyss
authors.affiliation: Department of Lead Discovery Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, Massachusetts 02141.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Soucy
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Chuan-Kui
authors.initials: CK
authors.lastname: Jiang
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
authors.forename: H-C
authors.initials: HC
authors.lastname: Huang
keywords: 2D 15N-HSQC; HCV NS5B polymerase; Hepatitis C virus; automated ligand identification system (ALIS); direct-acting antiviral (DAA); palm site inhibitors