A NOVEL PEROXYNITRITE SCAVENGER COMPOUND

一氧化氮(NO)和过氧亚硝酸盐是反应性的、短暂的物种，是各种形式的炎症和再灌注损伤的重要介质。最近的研究表明，NO和过氧亚硝酸盐在包括中风在内的各种形式的再灌注的发病机制中起着关键作用。伊诺克公司一直在开发各种以胍为基础的技术，用于治疗各种形式的炎症和再灌注损伤。Inote k的原型化合物之一--硫代乙基胍(Meg)，是一种选择性的诱导型一氧化氮合酶抑制剂和过氧亚硝酸根的清除剂，在各种炎症模型中证明了有效性。作为下一代的胍类药物，伊诺克建议制备和测试硒乙基胍。初步的体外数据表明，硫基被硒取代后，化合物与过氧亚硝酸根的反应活性增加了约100倍。此外，硒乙基胍维持其对一氧化氮合酶的抑制作用。本研究的第一个目的是合成硒乙基胍，并进行体外研究，以确定其作为一氧化氮合酶抑制剂的作用，测定其异构体选择性，以及其清除过氧亚硝酸根的活性。这项研究的第二个目的是在中风大鼠模型中测试硒乙基胍，在中风大鼠模型中，过氧亚硝酸根被认为在再灌注期的神经元坏死和凋亡中起关键作用。拟议的商业应用全球有效、安全的抗中风药物的市场估计为每年200亿美元，以200万患者为基础，每个疗程1万美元。预计在未来15年内，对有效治疗中风的需求将稳步增长。目前的市场进入者略微有效。

Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of various forms of inflammation and reperfusion injury. Recent studies have implicated the crucial role of NO and peroxynitrite in the pathogenesis of various forms of reperfusion, including stroke. Inotek Corporation has been developing various guanidine-based technologies for the treatment of various forms of inflammation and reperfusion injury. One of Inotek's prototype compounds, mercaptoethylguanidine (MEG) which is a selective inhibitor of the inducible nitric oxide synthase and scavenger of peroxynitrite, demonstrated efficacy in a variety of models of inflammation. As a next generation of guanidines, Inotek proposes to prepare and test selenoethylguanidine. Preliminary in vitro data demonstrated that substitution of the sulfur group by selenium increases the reactivity of the compound with peroxynitrite by about 100-fold. In addition, selenoethylguanidine maintains its NOS inhibitory effects. The first aim of the current study is to synthesize selenoethylguanidine, and perform in vitro studies to characterize its effects as NOS inhibitor, determine its isoform selectivity, and its peroxynitrite scavenging activity. The second aim of the study is to test selenoethylguanidine in a rat model of stroke, where peroxynitrite is known to play a key role in neuronal necrosis and apoptosis during the phase of reperfusion. PROPOSED COMMERCIAL APPLICATION Worldwide the market for an effective, safe anti-stroke pharmaceutical is estimated to be 20 billion dollars per year, based upon 2 million patients at 10,000 dollars per treatment course. The demand for effective treatment of stroke is expected to increase steadily over the next 15 years. Current market entrants are marginally effective.