title: Finger-loop inhibitors of the HCV NS5b polymerase. Part 1: Discovery and optimization of novel 1,6- and 2,6-macrocyclic indole series.
abstract: Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.
authors.affiliation: Janssen Infectious Diseases BVBA, 30 Turnhoutseweg, B-2340 Beerse, Belgium. dmcgowan@its.jnj.com
authors.forename: David
authors.initials: D
authors.lastname: McGowan
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vendeville
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Katie
authors.initials: K
authors.lastname: Amssoms
authors.forename: Jan Martin
authors.initials: JM
authors.lastname: Berke
authors.forename: Maxime
authors.initials: M
authors.lastname: Canard
authors.forename: Erna
authors.initials: E
authors.lastname: Cleiren
authors.forename: Pascale
authors.initials: P
authors.lastname: Dehertogh
authors.forename: Stefaan
authors.initials: S
authors.lastname: Last
authors.forename: Els
authors.initials: E
authors.lastname: Fransen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Van Der Helm
authors.forename: Iris
authors.initials: I
authors.lastname: Van den Steen
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rouan
authors.forename: Gregory
authors.initials: G
authors.lastname: Fanning
authors.forename: Origène
authors.initials: O
authors.lastname: Nyanguile
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Emelen
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase