Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors

[Display omitted] IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-09, Vol.26 (17), p.4250-4255
Main Authors: Hanisak, Jennifer, Seganish, W. Michael, McElroy, William T., Tang, Haiquin, Zhang, Rui, Tsui, Hon-Chung, Fischmann, Theirry, Tulshian, Deen, Tata, James, Sondey, Christopher, Devito, Kristine, Fossetta, James, Garlisi, Charles G., Lundell, Daniel, Niu, Xiaoda
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Animals
Binding Sites
Crystallography, X-Ray
Half-Life
Humans
Inflammation
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Interleukin receptor-associated kinases
Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors
Interleukin-1 Receptor-Associated Kinases - metabolism
IRAK4
Ligands
Molecular Dynamics Simulation
Protein Binding
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacokinetics
Protein Structure, Tertiary
Pyrazoles - chemistry
Pyrazoles - metabolism
Pyrazoles - pharmacokinetics
Rats
SAR
Structure-Activity Relationship
Toll-like receptors
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Summary:[Display omitted] IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.07.048