|
|||||
|
|
Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation |
|
| Authors: | Graham F Smith Michael D Altman Brian Andresen James Baker Jason D Brubaker Hongmin Chen Yiping Chen Matthew Childers Anthony Donofrio Heidi Ferguson Christian Fischer Thierry O Fischmann Craig Gibeau Alexander Hicks Sue Jin Sam Kattar Melanie A Kleinschek Erica Leccese Alan Northrup |
| Institution: | 1. AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States;2. Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States;3. Blueprint Medicines, 38 Sidney St Suite 200, Cambridge, MA 02139, United States;4. Oncorus, 50 Hampshire St. Suite 401, Cambridge, MA 02139, United States;5. Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, United States;6. Redx Pharma, Block 33, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom |
| Abstract: | Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation. |
| Keywords: | IRAK4 Quinazoline Serine-threonine kinase Kinase inhibitor Inflammatory disease HVQXFGHHSFTACS-CXIWYSOXSA-N |
| 本文献已被 ScienceDirect 等数据库收录！ | |