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Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

2017; Elsevier BV; Volume: 27; Issue: 12 Linguagem: Inglês

10.1016/j.bmcl.2017.04.050

1464-3405

G. Smith, Michael D. Altman, Brian M. Andresen, James Α. Baker, Jason D. Brubaker, Hongmin Chen, Yiping Chen, Matthew C. Childers, Anthony D’Onofrio, Heidi M. Ferguson, Christian Fischer, Thierry Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Solomon D. Kattar, Melanie A. Kleinschek, Erica Leccese, Charles A. Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John Maclean, Faruk Mansoor, Lilly Y. Moy, Erin F. Mulrooney, Antoaneta S. Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Ángel Pérula de Torres, Jie Zhang-Hoover, Alan B. Northrup,

Quinazolinone synthesis and applications

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.