title: Discovery of an irreversible HCV NS5B polymerase inhibitor.
abstract: The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.forename: Anilkumar G
authors.initials: AG
authors.lastname: Nair
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Rosenblum
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lesburg
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.forename: Tin-Yau
authors.initials: TY
authors.lastname: Chan
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Mousumi
authors.initials: M
authors.lastname: Sannigrahi
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.forename: Jose S
authors.initials: JS
authors.lastname: Duca
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Pu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrari
authors.forename: Chuan-kui
authors.initials: CK
authors.lastname: Jiang
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Hesk
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gesell
authors.forename: Steve
authors.initials: S
authors.lastname: Sorota
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000882:Haplorhini; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D011804:Quinolines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV; NS5B polymerase