Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

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• 作者：William T. McElroy ; Zheng Tan ; Ginny Ho ; Sunil Paliwal ; Guoqing Li ; W. Michael Seganish ; Deen Tulshian ; James Tata ; Thierry O. Fischmann ; Christopher Sondey ; Hong Bian ; Loretta Bober ; James Jackson ; Charles G. Garlisi ; Kristine Devito ; James Fossetta ; Daniel Lundell ; Xiaoda Niu
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：677-682
• 全文大小：384K
• ISSN：1948-5875

文摘

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.