Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 16; pp. 3203 - 3207
• Main Authors: Seganish, W. Michael, McElroy, William T., Herr, R. Jason, Brumfield, Stephanie, Greenlee, William J., Harding, James, Komanduri, Venukrishnan, Matasi, Julius, Prakash, Koraboina Chandra, Tulshian, Deen, Yang, Jinhai, Yet, Larry, Devito, Kristine, Fossetta, James, Garlisi, Charles G., Lundell, Daniel, Niu, Xiaoda, Sondey, Christopher
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2015; Elsevier
• Subjects: Aminopyrimidine; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; High-Throughput Screening Assays; Humans; Inflammation; Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors; IRAK4; Kinase; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Science & Technology; Structure activity relationships; Structure-Activity Relationship; Substrate Specificity; Toll-Like Receptor 4 - antagonists & inhibitors; Aminopyrimidine; Inflammation; IRAK4; Structure activity relationships; Kinase; IMMUNITY; INNATE; IRAK-4; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.05.097

[Display omitted] IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7nM, an IC50 of 55nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.