Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10595549 | Bioorganic & Medicinal Chemistry Letters | 2013 | 7 Pages |
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 (PI4KIIIÃ). 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.
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Authors
Anne Décor, Chantal Grand-Maître, Oliver Hucke, Jeff O'Meara, Cyrille Kuhn, Léa Constantineau -Forget, Christian Brochu, Eric Malenfant, Mégan Bertrand-Laperle, Josée Bordeleau, Elise Ghiro, Marc Pesant, Gulrez Fazal, Vida Gorys, Michael Little,