Development of DANDYs, New 3,5-Diaryl-7-azaindoles Demonstrating Potent DYRK1A Kinase Inhibitory Activity

详细信息    查看全文

• 作者：St茅phanie Gourdain ; Julien Dairou ; Cl茅ment Denhez ; Linh Chi Bui ; Fernando Rodrigues-Lima ; Nathalie Janel ; Jean M. Delabar ; Kevin Cariou ; Robert H. Dodd
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9569-9585
• 全文大小：850K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j鈥?b>l) demonstrated high inhibitory potencies with K_is in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10^鈥? M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.