Hypoxia Activated Nitric Oxide Donor Compounds for the Prevention and Treatment of Myocardial Hypoxia-Induced Injury

A series of hypoxia-targeted nitric oxide donor compounds were designed and synthesized by using an ether linker to connect <i>N</i>-methyl-<i>N</i>-nitroso-<i>p</i>-phenol and nitrobenzyl alcohols, respectively. Among them, <b>N6</b>, 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 <b>N6</b> could regulate vascular dilation and modulate proteins associated with myocardial injury both <i>in vitro</i> and <i>in vivo</i>. Animal tests demonstrated that <b>N6</b> showed better therapeutic and preventive effects against myocardial hypoxia injury than the commercial drug isosorbide mononitrate. Our research evidence that <b>N6</b> has a potent therapeutic potential in treating myocardial hypoxic injury, which can be further investigated as a promising drug candidate for coronary heart disease.