A NOVEL PEROXYNITRITE SCAVENGER COMPOUND

一种新型过氧亚硝酸盐清除剂化合物

• 批准号: 6015711
• 负责人: Garry John Southan
• 金额: $ 11.51万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-06 至 2000-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6015711
• 关键词: cardiovascular disorder chemotherapy; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; free radical scavengers; guanidines; laboratory rat; nitric oxide synthase; oxidoreductase inhibitor; peroxynitrites; reperfusion; selenium; stroke

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.

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和过氧亚硝酸盐在各种形式的再灌注，包括中风的发病机制中起着至关重要的作用。Inotek公司一直在开发各种基于胍的技术，用于治疗各种形式的炎症和再灌注损伤。 Inotek的原型化合物之一，巯基乙基胍（MEG），是一种诱导型一氧化氮合酶的选择性抑制剂和过氧亚硝酸盐的清除剂，在各种炎症模型中表现出有效性。 作为下一代胍，Inotek建议制备和测试硒乙基胍。 初步的体外数据表明，硒取代硫基团使化合物与过氧亚硝酸盐的反应性增加约100倍。 此外，硒乙基胍保持其NOS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，以表征其作为NOS抑制剂的作用，确定其异构体的选择性，以及其过氧亚硝酸根清除活性。 该研究的第二个目的是在中风大鼠模型中测试硒乙基胍，已知过氧亚硝酸盐在再灌注阶段的神经元坏死和细胞凋亡中发挥关键作用。根据200万名患者每疗程10，000美元的治疗费用，全球有效、安全的抗中风药物市场估计为每年200亿美元。 预计在未来15年内，对有效治疗中风的需求将稳步增长。 目前的市场进入者效果甚微。