4-（二氟甲基）- 1h -咪唑-5-羧酸/4-（3-氰苯氧基）嘧啶-5-羧酸作为缺血性脑卒中P2Y1受体拮抗剂的设计、合成和生物学评价

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-05-15 DOI:10.1021/acs.jmedchem.4c0311710.1021/acs.jmedchem.4c03117

Bing Zhang, Jinxin Li, Qi Li, Qiuhua Li, Ruyu Wang, Dan Liu, Xiwen Dai, Qing Mao, Xuefeng Fu, Wenhao Zha, Fengwei Lin, Chengjun Wu*, Yanhua Mou* and Shaojie Wang*,

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引用次数: 0

摘要

为了开发有效的缺血性卒中药物，化合物19 （IC50 = 0.49 μM）和36b （IC50 = 0.50 μM）作为我们之前报道的抗血小板药物HNW001的类似物，被鉴定为有效的P2Y1受体拮抗剂，优于HNW001和BPTU （IC50分别= 4.07和2.50 μM）。值得注意的是，这两种化合物通过上调核Nrf2蛋白水平在体外显示出显著的抗氧化应激神经保护作用。此外，化合物19和36b在大鼠体内表现出良好的血脑屏障穿透电位，大鼠MCAO模型显示它们能有效减小梗死面积，ED50值分别为8.39和4.60 mg/kg。同时，它们可以显著改善MCAO后的神经行为功能、脑含水量、氧化参数和海马组织损伤。因此，化合物19和36b是开发缺血性脑卒中有效药物的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Design, Synthesis, and Biological Evaluation of 4-(Difluoromethyl)-1H-imidazole-5-carboxylic Acids/4-(3-Cyanophenoxy)pyrimidine-5-carboxylic Acids as P2Y1 Receptor Antagonists for Ischemic Stroke Treatment

查看原文本刊更多论文

To develop effective agents for ischemic stroke, compounds 19 (IC₅₀ = 0.49 μM) and 36b (IC₅₀ = 0.50 μM), as analogues of our previously reported antiplatelet agent HNW001, were identified as potent P2Y₁ receptor antagonists, which were superior to HNW001 and BPTU (IC₅₀ = 4.07 and 2.50 μM, respectively). Notably, these two compounds showed remarkable neuroprotective potency against oxidative stress by upregulating nuclear Nrf2 protein levels in vitro. Additionally, compounds 19 and 36b demonstrated favorable blood-brain barrier penetration potential in rats, and the rat MCAO model showed that they could effectively reduce infarction sizes with ED₅₀ values of 8.39 and 4.60 mg/kg, respectively. Meanwhile, they could remarkably ameliorate neurobehavioral function, brain water content, oxidative parameters, and hippocampal tissue damage following MCAO. Thus, compounds 19 and 36b were promising lead compounds for developing effective agents to treat ischemic stroke.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.