Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors

详细信息    查看全文

• 作者：W. Michael Seganish ; Thierry O. Fischmann ; Brad Sherborne ; Julius Matasi ; Brian Lavey ; William T. McElroy ; Deen Tulshian ; James Tata ; Christopher Sondey ; Charles G. Garlisi ; Kristine Devito ; James Fossetta ; Daniel Lundell ; Xiaoda Niu
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：942-947
• 全文大小：438K
• ISSN：1948-5875

文摘

We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC₅₀ = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC₅₀ = 93 nM) and good rat bioavailability (F = 42%).