Discovery of Pyridone-Substituted Triazolopyrimidine Dual A(2A)/A(1) AR Antagonists for the Treatment of Ischemic Stroke.
Discovery of Pyridone-Substituted Triazolopyrimidine Dual A(2A)/A(1) AR Antagonists for the Treatment of Ischemic Stroke.
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发现吡啶酮取代的三唑并嘧啶双重 A2A/A1 AR 拮抗剂用于治疗缺血性中风
DOI：
10.1021/acsmedchemlett.1c00599
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发表时间：
2022-03-10
影响因子：
4.2
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Tang ML;Wen ZH;Wang JH;Wang ML;Zhang H;Liu XH;Jin L;Chang J
缺血性卒中是一种高发病率、高致残率、高死亡率的复杂全身性疾病。突触前腺苷A2A和A1受体的激活改变了从兴奋性毒性到中风的各种脑损伤。因此，发现双A2A/A1腺苷受体(AR)靶向治疗化合物可能成为治疗缺血性卒中的一种策略。受两种临床三期药物ASP-5854(双A2A/A1 AR拮抗剂)和前儿药(选择性A2AAR拮抗剂)的启发，采用混合药物策略，我们将新型吡啶酮取代的三唑并嘧啶类支架表征为双A2A/A1 AR拮抗剂。其中，化合物1a在人、大鼠和狗肝微粒体中表现出良好的A2A/A1 AR结合亲和力(Ki=5.58/24.2 nM)、拮抗作用(IC50=5.72/25.9 nM)和良好的代谢稳定性。重要的是，化合物1a在缺氧-葡萄糖剥夺/再灌注(OGD/R)处理的HT22细胞模型中表现出剂量-效应关系。这些发现支持开发双A2A/A1 AR拮抗剂作为治疗缺血性中风的潜在方法。
Ischemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A2A and A1 receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A2A/A1 adenosine receptor (AR)-targeting therapeutic compounds could be a strategy for the treatment of ischemic stroke. Inspired by two clinical phase III drugs, ASP-5854 (dual A2A/A1 AR antagonist) and preladenant (selective A2A AR antagonist), and using the hybrid medicinal strategy, we characterized novel pyridone-substituted triazolopyrimidine scaffolds as dual A2A/A1 AR antagonists. Among them, compound 1a exerted excellent A2A/A1 AR binding affinity (Ki = 5.58/24.2 nM), an antagonistic effect (IC50 = 5.72/25.9 nM), and good metabolic stability in human liver microsomes, rat liver microsomes, and dog liver microsomes. Importantly, compound 1a demonstrated a dose–effect relationship in the oxygen-glucose deprivation/reperfusion (OGD/R)-treated HT22 cell model. These findings support the development of dual A2A/A1 AR antagonists as a potential treatment for ischemic stroke.
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影响因子：
4.2
作者：
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通讯作者：
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影响因子：
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作者：
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实验中风后神经炎症中腺苷A（1）受体的体内多模式成像。
影响因子：
12.4
作者：
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