title: Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus.
abstract: We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5.
authors.forename: Anne
authors.initials: A
authors.lastname: Décor
authors.forename: Chantal
authors.initials: C
authors.lastname: Grand-Maître
authors.forename: Oliver
authors.initials: O
authors.lastname: Hucke
authors.forename: Jeff
authors.initials: J
authors.lastname: O'Meara
authors.forename: Cyrille
authors.initials: C
authors.lastname: Kuhn
authors.forename: Léa
authors.initials: L
authors.lastname: Constantineau-Forget
authors.forename: Christian
authors.initials: C
authors.lastname: Brochu
authors.forename: Eric
authors.initials: E
authors.lastname: Malenfant
authors.forename: Mégan
authors.initials: M
authors.lastname: Bertrand-Laperle
authors.forename: Josée
authors.initials: J
authors.lastname: Bordeleau
authors.forename: Elise
authors.initials: E
authors.lastname: Ghiro
authors.forename: Marc
authors.initials: M
authors.lastname: Pesant
authors.forename: Gulrez
authors.initials: G
authors.lastname: Fazal
authors.forename: Vida
authors.initials: V
authors.lastname: Gorys
authors.forename: Michael
authors.initials: M
authors.lastname: Little
authors.forename: Colette
authors.initials: C
authors.lastname: Boucher
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bordeleau
authors.forename: Pascal
authors.initials: P
authors.lastname: Turcotte
authors.forename: Tim
authors.initials: T
authors.lastname: Guo
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Catherine
authors.initials: C
authors.lastname: Spickler
authors.forename: Annick
authors.initials: A
authors.lastname: Gauthier
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012229:Rhinovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D013844:Thiazoles