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

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

  • Bioorg Chem. 2023 Aug;137:106584. doi: 10.1016/j.bioorg.2023.106584.
Yongjin Hao 1,  Jin Wang 1,  Jiawan Ma 1,  Xiaoliang Yu 2,  Zhanhui Li 1,  Shuwei Wu 3,  Sheng Tian 1,  Haikuo Ma 1,  Sudan He 4,  Xiaohu Zhang 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, P. R. China.
  • 2 CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, 100005, P. R. China; Suzhou Institute of Systems Medicine, Suzhou, 215123 Jiangsu, P. R. China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, P. R. China. Electronic address: [email protected].
  • 4 CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, 100005, P. R. China; Suzhou Institute of Systems Medicine, Suzhou, 215123 Jiangsu, P. R. China; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, P. R. China. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, P. R. China. Electronic address: [email protected].
PMID: 37163814 DOI: 10.1016/j.bioorg.2023.106584
Abstract

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.

Keywords

5-b]pyridine scaffold; IRAK4; Inflammation; Innate immunity; Kinase inhibitor; Oxazolo[4; hERG.

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