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

被引：21

作者：

Decor, Anne ^{[1
]}

Grand-Maitre, Chantal ^{[1
]}

Hucke, Oliver ^{[1
]}

O'Meara, Jeff ^{[1
]}

Kuhn, Cyrille ^{[1
]}

Constantineau-Forget, Lea ^{[2
]}

Brochu, Christian ^{[1
]}

Malenfant, Eric ^{[1
]}

Bertrand-Laperle, Megan ^{[1
]}

Bordeleau, Josee ^{[1
]}

Ghiro, Elise ^{[1
]}

Pesant, Marc ^{[1
]}

Fazal, Gulrez ^{[1
]}

Gorys, Vida ^{[1
]}

Little, Michael ^{[1
]}

Boucher, Colette ^{[1
]}

Bordeleau, Sylvain ^{[1
]}

Turcotte, Pascal ^{[1
]}

Guo, Tim ^{[1
]}

Garneau, Michel ^{[1
]}

Spickler, Catherine ^{[1
]}

Gauthier, Annick ^{[1
]}

机构：

[1] Boehringer Ingelheim Canada Ltd, Res & Dev, Laval, PQ H7S 2G5, Canada

[2] Univ Montreal, Dept Chem, Montreal, PQ H3C 3J7, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 13期

关键词：

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

D O I：

10.1016/j.bmcl.2013.04.077

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (c) 2013 Elsevier Ltd. All rights reserved.

引用

页码：3841 / 3847

页数：7

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