title: Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein.
abstract: Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5nM and 1.2nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9nM and 6.1nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's=10.2 and 30.4nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.
authors.affiliation: GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Electronic address: vincent.w.tai@gsk.com.
authors.forename: Vincent W-F
authors.initials: VW
authors.lastname: Tai
authors.affiliation: GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Dulce
authors.initials: D
authors.lastname: Garrido
authors.affiliation: GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Price
authors.affiliation: GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Maynard
authors.affiliation: GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Pouliot
authors.affiliation: GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Seal
authors.affiliation: GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Creech
authors.affiliation: GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Luz H
authors.initials: LH
authors.lastname: Kryn
authors.affiliation: GlaxoSmithKline, Anti Bacterial Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Baughman
authors.affiliation: GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D058990:Molecular Targeted Therapy; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C080107:NS4B protein, flavivirus; D013141:Spiro Compounds; D017361:Viral Nonstructural Proteins
keywords: Hepatitis C virus (HCV); NS4B; Pyrazolo[1,5-a]pyridine; Replication inhibitors; Spirocyclic ketals