| Literature DB >> 28501511 |
Graham F Smith1, Michael D Altman2, Brian Andresen2, James Baker2, Jason D Brubaker3, Hongmin Chen2, Yiping Chen2, Matthew Childers2, Anthony Donofrio2, Heidi Ferguson2, Christian Fischer2, Thierry O Fischmann2, Craig Gibeau2, Alexander Hicks4, Sue Jin2, Sam Kattar2, Melanie A Kleinschek5, Erica Leccese2, Charles Lesburg2, Chaomin Li2, Jongwon Lim6, Duan Liu2, John K F Maclean7, Faruk Mansoor2, Lilly Y Moy2, Erin F Mulrooney2, Antoaneta S Necheva2, Jeremy Presland2, Larissa Rakhilina2, Ruojing Yang2, Luis Torres2, Jie Zhang-Hoover2, Alan Northrup2.
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.Entities:
Keywords: IRAK4; Inflammatory disease; Kinase inhibitor; Quinazoline; Serine-threonine kinase
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Year: 2017 PMID： 28501511 DOI： 10.1016/j.bmcl.2017.04.050
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823