title: Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate.
abstract: Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
authors.affiliation: Infectious Diseases CEDD and Medicinal Discovery Research, GlaxoSmithKline, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. martin.j.slater@gsk.com
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Slater
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Amphlett
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Bravi
authors.forename: George
authors.initials: G
authors.lastname: Burton
authors.forename: Anne G
authors.initials: AG
authors.lastname: Cheasty
authors.forename: John A
authors.initials: JA
authors.lastname: Corfield
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Ellis
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Fenwick
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fernandes
authors.forename: Rossella
authors.initials: R
authors.lastname: Guidetti
authors.forename: David
authors.initials: D
authors.lastname: Haigh
authors.forename: C David
authors.initials: CD
authors.lastname: Hartley
authors.forename: Peter D
authors.initials: PD
authors.lastname: Howes
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Jackson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Jarvest
authors.forename: Victoria L H
authors.initials: VL
authors.lastname: Lovegrove
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Medhurst
authors.forename: Nigel R
authors.initials: NR
authors.lastname: Parry
authors.forename: Helen
authors.initials: H
authors.lastname: Price
authors.forename: Pritom
authors.initials: P
authors.lastname: Shah
authors.forename: Onkar M P
authors.initials: OM
authors.lastname: Singh
authors.forename: Richard
authors.initials: R
authors.lastname: Stocker
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.forename: Claire
authors.initials: C
authors.lastname: Wilkinson
authors.forename: Alan
authors.initials: A
authors.lastname: Wonacott
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D002522:Chlorocebus aethiops; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D011759:Pyrrolidines; D012324:RNA-Dependent RNA Polymerase