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

被引：6

作者：

Hao, Yongjin ^{[1
]}

Wang, Jin ^{[1
]}

Ma, Jiawan ^{[1
]}

Yu, Xiaoliang ^{[2
,3
]}

Li, Zhanhui ^{[1
]}

Wu, Shuwei ^{[1
]}

Tian, Sheng ^{[1
]}

Ma, Haikuo ^{[1
]}

He, Sudan ^{[2
,3
,4
]}

Zhang, Xiaohu ^{[1
]}

机构：

[1] Soochow Univ, Coll Pharmaceut Sci, Jiangsu Key Lab Neuropsychiat Dis, Suzhou 215123, Jiangsu, Peoples R China

[2] Inst Syst Med, Chinese Acad Med Sci & Peking Union Medial Coll, CAMS Key Lab Synthet Biol Regulatory Elements, Beijing 100005, Peoples R China

[3] Suzhou Inst Syst Med, Suzhou 215123, Jiangsu, Peoples R China

[4] Inst Basic Med Sci, Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Med Mol Biol, Beijing, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2023年 / 137卷

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

Innate immunity; Inflammation; IRAK4; Kinase inhibitor; hERG; Oxazolo[4; b ]pyridine scaffold; KINASE; 4; IN-VIVO; MEDICINAL CHEMISTRY; ANIMAL-MODELS; RECOGNITION; DISCOVERY; MYD88; DRUGS;

D O I：

10.1016/j.bioorg.2023.106584

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 rela-tionship (SAR) studies, a series of IRAK4 inhibitors with oxazolo[4,5-b]pyridine scaffold were identified. Com-pound 32 showed improved potency (IC50 = 43 nM) compared to CA-4948 (IC50 = 115 nM), but suffered from hERG inhibition (IC50 = 5.7 mu M). Further optimization led to compound 42 with reduced inhibition of hERG (IC50 > 30 mu M) 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-alpha 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.

引用

页数：17

共 51 条

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