Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer's Disease

被引：8

作者：

Chen, Huanhua ^{[1
]}

Gao, Xudong ^{[3
]}

Li, Xinzhu ^{[2
]}

Yu, Chong ^{[1
]}

Liu, Wenwu ^{[1
]}

Qiu, Jingsong ^{[1
]}

Liu, Wenjie ^{[1
]}

Geng, Hefeng ^{[2
]}

Zheng, Fangyuan ^{[2
]}

Gong, Hao ^{[1
]}

Xu, Zihua ^{[1
]}

Jia, Jingming ^{[1
]}

Zhao, Qingchun ^{[1
,2
,3
]}

机构：

[1] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Shenyang 110016, Liaoning, Peoples R China

[2] Shenyang Pharmaceut Univ, Sch Life Sci & Biochem, Shenyang 110016, Liaoning, Peoples R China

[3] Gen Hosp Northern Theater Command, Dept Pharm, Shenyang 110840, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 15期

基金：

中国国家自然科学基金;

关键词：

GLYCOGEN-SYNTHASE KINASE-3; SPATIAL MEMORY IMPAIRMENT; DOWN-SYNDROME; TAU-PHOSPHORYLATION; DYRK1A INHIBITOR; DRUG DISCOVERY; PROTEIN; MECHANISM; SUPPORT; RESCUES;

D O I：

10.1021/acs.jmedchem.4c00483

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.

引用

页码：12571 / 12600

页数：30

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