NOVEL NO SCAVENGER FOR THE EXPERIMENTAL THERAPY OF PD

- 你好一氧化氮（NO）和过氧亚硝酸盐是反应性的、短寿命的物质，其是各种形式的炎症的重要介质。 最近的研究表明，NO和过氧亚硝酸盐在各种形式的神经退行性疾病（包括帕金森病）的发病机制中起着至关重要的作用。 Inotek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巨大的益处，包括实验性自身免疫性脑脊髓炎和内毒素休克。 这类化合物的例子有2-苯基-4，4，5，5-四甲基-咪唑啉氧基-1-氧基-3-氧化物（PTIO）及其水溶性衍生物羧基-PTIP（c-PTIO）。 羧基-PTIO清除过量的NO产生，并在这样做的过程中，防止形成有毒量的过氧亚硝酸盐，这是一种导致细胞功能障碍和器官衰竭的反应性氧化剂。 羧基-PTIO还对过氧亚硝酸根具有直接的蛋白质清除作用。 本提案的具体目的是在帕金森病的鼠模型中进行确定性的体内研究，以测试羧基-PTIO是否可以被开发用于这种病症的实验治疗。 本申请的结果将允许申请2期SBIR资金，以支持：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申请研究药物和1期临床试验。 拟议的商业应用：一种治疗帕金森病的新型有效疗法的国内市场 保守估计每年为5 000万美元。全球市场估计为150美元 万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.