title: Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127).
abstract: Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.
authors.affiliation: Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5.
authors.forename: Steven R
authors.initials: SR
authors.lastname: LaPlante
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.forename: Christian
authors.initials: C
authors.lastname: Brochu
authors.forename: Catherine
authors.initials: C
authors.lastname: Chabot
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: James R
authors.initials: JR
authors.lastname: Gillard
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.forename: Martin
authors.initials: M
authors.lastname: Poirier
authors.forename: Jean
authors.initials: J
authors.lastname: Rancourt
authors.forename: Timothy
authors.initials: T
authors.lastname: Stammers
authors.forename: Bounkham
authors.initials: B
authors.lastname: Thavonekham
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase