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 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.