NOVEL NO SCAVENGER FOR THE EXPERIMENTAL THERAPY OF PD

(申请人摘要)一氧化氮(NO)和过氧亚硝酸盐是反应性的、短暂的物种，是各种形式炎症的重要介质。最近的研究表明，NO和过氧亚硝酸盐在包括帕金森病在内的各种形式的神经退行性疾病的发病机制中起着关键作用。伊诺克公司正在开发一种独特的NO清除剂--羧基PTIO，根据初步数据，它在各种严格的炎症模型中产生了显著的好处，包括实验性自身免疫性脑脊髓炎和内毒素休克。这类化合物以2-phenyl-4，4，5，5-tetramethyl-imidazolineoxyl-1-oxyl-3-oxide(PTIO)及其水溶性衍生物--羧基PTIP(c-PTIO)为代表。Carboxy-PTIO清除过量的NO产生，并在这样做的过程中，防止形成有毒数量的过氧亚硝酸盐，过氧亚硝酸盐是一种活性氧化剂，会导致细胞功能障碍和器官衰竭。羧基PTIO对过亚硝酸根也有明显的直接清除作用。本提案的具体目的是在帕金森病小鼠模型上进行明确的体内研究，以测试是否可以开发出羧基PTIO用于该疾病的实验性治疗。本申请的结果将允许应用第二阶段SBIR资金来支持：临床前药物测试(高级毒性测定、病理学、稳定性、药代动力学、体内疗效)、向FDA申请研究药物，以及第一阶段临床试验。建议的商业应用：帕金森病的一种新的、有效的治疗方法的国内市场 保守估计为每年5000万美元。据估计，全球市场价值150美元。 百万美元。SBIR第一和第二阶段的资金将允许在3.5年内进入市场。

DESCRIPITON: (Applicant's abstract) Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of various forms of inflammation. Recent studies have implicated the crucial role of NO and peroxynitrite in the pathogenesis of various forms of neurodegenerative disorders, including Parkinson's disease. Inotek Corporation is developing a unique NO scavenger, carboxy-PTIO, which, according to preliminary data, produces dramatic benefits in a variety of stringent inflammatory models, including experimental autoimmune encephalomyelitis and endotoxic shock. This class is exemplified by 2-phenyl-4,4,5,5-tetramethyl-imidazolineoxyl-1-oxyl-3-oxide (PTIO) and its water-soluble derivative, carboxy-PTIP (c-PTIO). Carboxy-PTIO scavenges excessive NO production and, in so doing, prevents the formation of toxic quantities of peroxynitrite, a reactive oxidant which causes cell dysfunction and organ failure. Carboxy-PTIO also has a direct protent scavenging effect on peroxynitrite. The specific aim of the present proposal is to perform definitive in vivo studies in murine model of Parkinson's disease in order to test whether carboxy-PTIO can be developed for the experimental therapy of this condition. The results of the present application will permit application of Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA, and a Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATION: The domestic market for a novel, effective therapy for Parkinson's disease is conservatively estimated at $50 million per annum. Global markets are estimated at $150 million. Funding of SBIR Phases I and II will allow for market entry in 3.5 years.