Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors

详细信息    查看全文

• 作者：Sharada Labadie ; Kathy Barrett ; Wade S. Blair ; Christine Chang ; Gauri Deshmukh ; Charles Eigenbrot ; Paul Gibbons ; Adam Johnson ; Jane R. Kenny ; Pawan Bir Kohli ; Marya Liimatta ; Patrick J. Lupardus ; Steven Shia ; Micah Steffek ; Savita Ubhayakar ; Anne van Abbema ; Mark Zak
• 关键词：JAK inhibitors ; 8-Oxo-pyridopyrimidines ; Rheumatoid arthritis ; Hematopoiesis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 November, 2013
• 年：2013
• 卷：23
• 期：21
• 页码：5923-5930
• 全文大小：3679 K

文摘

A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.