Design, synthesis, evaluation and optimization of potent IRAK4 inhibitors alleviating production of inflammatory cytokines in LPS-induced SIRS model.

Interleukin-1 receptor associated kinase-4 (IRAK4) has emerged as a therapeutic target for inflammatory and autoimmune diseases. Through reversing the amide of CA-4948 and computer aided structure-activity relationship (SAR) studies, a series of IRAK4 inhibitors with oxazolo[4,5-b]pyridine scaffold were identified. Compound 32 showed improved potency (IC ₅₀  = 43 nM) compared to CA-4948 (IC ₅₀  = 115 nM), but suffered from hERG inhibition (IC ₅₀  = 5.7 μM). Further optimization led to compound 42 with reduced inhibition of hERG (IC ₅₀  > 30 μM) and 13-fold higher activity (IC ₅₀  = 8.9 nM) than CA-4948. Importantly, compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties. Furthermore, compound 42 significantly reduced LPS-induced production of serum TNF-α and IL-6 cytokines in the mouse model. The overall profiles of compound 42 support it as a lead for the development of IRAK4 inhibitors for the treatment of inflammatory and autoimmune disorders.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Shuwei Wu reports financial support was provided by China Postdoctoral Science foundation. Xiaohu Zhang, Sudan He reports financial support was provided by National Natural Science Foundation of China. Xiaohu Zhang reports financial support was provided by the Priority Academic Program Development of the Jiangsu Higher Education Institutes. Xiaohu Zhang reports financial support was provided by the Jiangsu Key Laboratory of Neuropsychiatric Diseases. Sudan He reports financial support was provided by the CAMS Innovation Fund for Medical Sciences. Sudan He reports financial support was provided by Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences. Xiaohu Zhang, Sudan He reports financial support was provided by Accro Bioscience. Xiaohu Zhang, Sudan He has patent pending to Accro Bioscience(Shuwei Wu, Xiaohu Zhang, Sudan He)].
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