Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 547.2 Organic chemical reactions formerly 547.139
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 942-947 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261175
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Inhibitors; 4. Peptides and proteins; 5. Piperidines; 6. Pyrimidine; 7. Selectivity

Tóm tắt

 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 (IC<
 sub>
 50<
 /sub>
  = 27 nM) and excellent kinase selectivity (>
 100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC<
 sub>
 50<
 /sub>
  = 93 nM) and good rat bioavailability (F = 42%).