title: Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound.
abstract: Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
authors.affiliation: GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Andrew
authors.initials: A
authors.lastname: Maynard
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.forename: Sam
authors.initials: S
authors.lastname: Baskaran
authors.forename: Janos
authors.initials: J
authors.lastname: Botyanszki
authors.forename: Renae
authors.initials: R
authors.lastname: Crosby
authors.forename: Scott
authors.initials: S
authors.lastname: Dickerson
authors.forename: Matthew
authors.initials: M
authors.lastname: Tallant
authors.forename: Rick
authors.initials: R
authors.lastname: Grimes
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Martin
authors.initials: M
authors.lastname: Leivers
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Roberts
authors.forename: Jill
authors.initials: J
authors.lastname: Walker
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D009154:Mutation; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D011759:Pyrrolidines; D012367:RNA, Viral; D013141:Spiro Compounds