title: Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity.
abstract: The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.
authors.affiliation: Department of Medicinal Chemistry, Merck and Company, Inc. West Point, PA 19486 (USA). craig_coburn@merck.com.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Wei
authors.initials: W
authors.lastname: Chang
authors.forename: Christine M
authors.initials: CM
authors.lastname: Fandozzi
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Graham
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Joseph
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Dahai
authors.initials: D
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhong
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007211:Indoles / Q000737:chemistry; D009154:Mutation; D002679:Pan troglodytes; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D017361:Viral Nonstructural Proteins; C000589335:elbasvir; C030374:indole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: antiviral agents; hepatitis C; inhibitors; medicinal chemistry; structure-activity relationships