Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

作者：Decor Anne; Grand Maitre Chantal; Hucke Oliver^*; O'Meara Jeff; Kuhn Cyrille; Constantineau Forget Lea; Brochu Christian; Malenfant Eric; Bertrand Laperle Megan; Bordeleau Josee; Ghiro Elise; Pesant Marc; Fazal Gulrez; Gorys Vida; Little Michael; Boucher Colette; Bordeleau Sylvain; Turcotte Pascal; Guo Tim; Garneau Michel; Spickler Catherine; Gauthier Annick

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(13): 3841-3847.

DOI：10.1016/j.bmcl.2013.04.077

• Human rhinovirus
• HRV
• Library design
• Aminothiazoles
• Design of experiment
• DOE
• PI4KIII beta

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 (PI4KIII beta). 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.

• 出版日期2013-7-1