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

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 12; pp. 2721 - 2726
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2017; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Administration, Oral; Animals; BASIC BIOLOGICAL SCIENCES; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Disease Models, Animal; Dose-Response Relationship, Drug; High-Throughput Screening Assays; Imidazoles - pharmacology; Inflammation - drug therapy; Inflammation - enzymology; Inflammatory disease; Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors; Interleukin-1 Receptor-Associated Kinases - metabolism; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - biosynthesis; IRAK4; Kinase inhibitor; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quinazoline; Quinazolines - administration & dosage; Quinazolines - chemistry; Quinazolines - pharmacology; Rats; Rats, Inbred Lew; Science & Technology; Serine-threonine kinase; Structure-Activity Relationship; HVQXFGHHSFTACS-CXIWYSOXSA-N; IRAK4; Quinazoline; Kinase inhibitor; Serine-threonine kinase; Inflammatory disease; RHEUMATOID-ARTHRITIS; INTERLEUKIN-1; KINASE 4; MOLECULE; MEDIATOR; DISCOVERY; FAMILY; COLITIS; OPTIMIZATION; INNATE IMMUNITY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.04.050

[Display omitted] 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.