A series of hypoxia-targeted nitric oxide donor compounds were designed and synthesized by using an ether linker to connect N-methyl-N-nitroso-p-phenol and nitrobenzyl alcohols, respectively. Among them, N6, with acceptable pharmacokinetic parameters in mice, exhibited a high selective NO release in H9c2 cells under hypoxia and in the dissected heart tissue of the tested mice as desired. Mechanistic investigations revealed that N6 could regulate vascular dilation and modulate proteins associated with myocardial injury both in vitro and in vivo. Animal tests demonstrated that N6 showed better therapeutic and preventive effects against myocardial hypoxia injury than the commercial drug isosorbide mononitrate. Our research evidence that N6 has a potent therapeutic potential in treating myocardial hypoxic injury, which can be further investigated as a promising drug candidate for coronary heart disease.

中文翻译：

---

缺氧活化的一氧化氮供体化合物用于预防和治疗心肌缺氧诱导的损伤


通过使用醚接头分别连接 N-甲基-N-亚硝基对苯酚和硝基苄醇，设计合成了一系列缺氧靶向一氧化氮供体化合物。其中，N6 在小鼠中具有可接受的药代动力学参数，在缺氧下在 H9c2 细胞中和受试小鼠的解剖心脏组织中表现出高选择性 NO 释放。机制调查显示，N6 可以在体外和体内调节血管扩张和调节与心肌损伤相关的蛋白质。动物试验表明，N6 对心肌缺氧损伤的治疗和预防作用优于市售药物单硝酸异山梨酯。我们的研究证据表明，N6 在治疗心肌缺氧损伤方面具有强大的治疗潜力，可以作为冠心病的有前途的候选药物进一步研究。