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

• Published in: Bioorganic chemistry 2023-08, Vol.137, p.106584-106584, Article 106584
• Main Authors: Hao, Yongjin, Wang, Jin, Ma, Jiawan, Yu, Xiaoliang, Li, Zhanhui, Wu, Shuwei, Tian, Sheng, Ma, Haikuo, He, Sudan, Zhang, Xiaohu
• Format: Article
• Language: English
• Subjects: 5-b]pyridine scaffold; hERG; Inflammation; Innate immunity; IRAK4; Kinase inhibitor; Oxazolo
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106584

[Display omitted] •Potent IRAK4 inhibitors were synthesized based on CA-4948.•Structural optimization mitigated hERG activity while improved IRAK4 inhibition.•Compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties.•Compound 42 significantly reduced LPS-induced cytokine release in mouse 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 (IC50 = 43 nM) compared to CA-4948 (IC50 = 115 nM), but suffered from hERG inhibition (IC50 = 5.7 μM). Further optimization led to compound 42 with reduced inhibition of hERG (IC50 > 30 μM) and 13-fold higher activity (IC50 = 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.