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

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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404982
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry Letters; Journal Volume: 27; Journal Issue: 12
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Smith, Graham F., Altman, Michael D., Andresen, Brian, Baker, James, Brubaker, Jason D., Chen, Hongmin, Chen, Yiping, Childers, Matthew, Donofrio, Anthony, Ferguson, Heidi, Fischer, Christian, Fischmann, Thierry O., Gibeau, Craig, Hicks, Alexander, Jin, Sue, Kattar, Sam, Kleinschek, Melanie A., Leccese, Erica, Lesburg, Charles, Li, Chaomin, Lim, Jongwon, Liu, Duan, Maclean, John K. F., Mansoor, Faruk, Moy, Lilly Y., Mulrooney, Erin F., Necheva, Antoaneta S., Presland, Jeremy, Rakhilina, Larissa, Yang, Ruojing, Torres, Luis, Zhang-Hoover, Jie, and Northrup, Alan. Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation. United States: N. p., 2017. Web. doi:10.1016/j.bmcl.2017.04.050.
Smith, Graham F., Altman, Michael D., Andresen, Brian, Baker, James, Brubaker, Jason D., Chen, Hongmin, Chen, Yiping, Childers, Matthew, Donofrio, Anthony, Ferguson, Heidi, Fischer, Christian, Fischmann, Thierry O., Gibeau, Craig, Hicks, Alexander, Jin, Sue, Kattar, Sam, Kleinschek, Melanie A., Leccese, Erica, Lesburg, Charles, Li, Chaomin, Lim, Jongwon, Liu, Duan, Maclean, John K. F., Mansoor, Faruk, Moy, Lilly Y., Mulrooney, Erin F., Necheva, Antoaneta S., Presland, Jeremy, Rakhilina, Larissa, Yang, Ruojing, Torres, Luis, Zhang-Hoover, Jie, & Northrup, Alan. Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation. United States. doi:10.1016/j.bmcl.2017.04.050.
Smith, Graham F., Altman, Michael D., Andresen, Brian, Baker, James, Brubaker, Jason D., Chen, Hongmin, Chen, Yiping, Childers, Matthew, Donofrio, Anthony, Ferguson, Heidi, Fischer, Christian, Fischmann, Thierry O., Gibeau, Craig, Hicks, Alexander, Jin, Sue, Kattar, Sam, Kleinschek, Melanie A., Leccese, Erica, Lesburg, Charles, Li, Chaomin, Lim, Jongwon, Liu, Duan, Maclean, John K. F., Mansoor, Faruk, Moy, Lilly Y., Mulrooney, Erin F., Necheva, Antoaneta S., Presland, Jeremy, Rakhilina, Larissa, Yang, Ruojing, Torres, Luis, Zhang-Hoover, Jie, and Northrup, Alan. Thu . "Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation". United States. doi:10.1016/j.bmcl.2017.04.050.
@article{osti_1404982,
title = {Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation},
author = {Smith, Graham F. and Altman, Michael D. and Andresen, Brian and Baker, James and Brubaker, Jason D. and Chen, Hongmin and Chen, Yiping and Childers, Matthew and Donofrio, Anthony and Ferguson, Heidi and Fischer, Christian and Fischmann, Thierry O. and Gibeau, Craig and Hicks, Alexander and Jin, Sue and Kattar, Sam and Kleinschek, Melanie A. and Leccese, Erica and Lesburg, Charles and Li, Chaomin and Lim, Jongwon and Liu, Duan and Maclean, John K. F. and Mansoor, Faruk and Moy, Lilly Y. and Mulrooney, Erin F. and Necheva, Antoaneta S. and Presland, Jeremy and Rakhilina, Larissa and Yang, Ruojing and Torres, Luis and Zhang-Hoover, Jie and Northrup, Alan},
abstractNote = {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.},
doi = {10.1016/j.bmcl.2017.04.050},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 12,
volume = 27,
place = {United States},
year = {Thu Jun 01 00:00:00 EDT 2017},
month = {Thu Jun 01 00:00:00 EDT 2017}
}