NOVEL PARS INHIBITOR FOR THE EXPERIMENTAL THERAPY OF PD

用于 PD 实验治疗的新型 PARS 抑制剂

• 批准号: 2793080
• 负责人: JON G MABLEY
• 金额: $ 10万
• 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: 1999-05-10 至 1999-11-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2793080
• 关键词: ADP ribosylation; Parkinson's disease; adenine phosphoribosyltransferase; brain disorder diagnosis; disease /disorder model; drug design /synthesis /production; enzyme inhibitors; high performance liquid chromatography; immunocytochemistry; laboratory mouse; neuroprotectants

DESCRIPTION: (Applicant's abstract) A recently discovered mechanism of inflammatory injury, the "poly (ADP-ribose) synthetase (PARS) pathway," has been implicated in the pathogenesis of various forms of neuronal injury. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. The applicants have developed a novel class of compounds with neuroprotective potential. In this proposal, we present evidence that INH2BP, a potent non-toxic PARS inhibitor, reduces oxidant-induced cellular injury. Furthermore, we present evidence for the role of PARS in a murine model of stroke. Inotek's long-term intention to develop INH2BP as a drug for the treatment of neuroinjury. 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 INH2BP can be developed for the experimental therapy of this condition. The results of the present application will permit application for the 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 Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATION: Novel drugs for the therapy of Parkinson's Disease.

描述：（申请人的摘要）最近发现的一种抗肿瘤的机制， 炎症损伤，“聚（ADP-核糖）合成酶（PARS）途径”， 与各种形式的神经元损伤的发病机制有关。 由氧化剂诱导的DNA单链断裂触发，PARS催化一种 ADP-核糖的耗能聚合，导致NAD耗尽， 抑制糖酵解和线粒体呼吸， 细胞内高能磷酸盐的减少。申请人已经 开发了一类具有神经保护潜力的新型化合物。在这 建议，我们提出的证据表明，INH 2BP，一种有效的无毒PARS抑制剂， 减少氧化剂诱导的细胞损伤。此外，我们还提供了证据， PARS在小鼠中风模型中的作用。Inotek的长期意图是 开发INH 2BP作为治疗神经损伤的药物。具体目标是 本发明建议在鼠模型中进行确定性体内研究 为了测试INH 2BP是否可以被开发用于帕金森病， 这种情况的实验疗法。本申请的结果 将允许申请2期SBIR资金，以支持： 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）、研究药物应用于 FDA和1期临床试验。 拟定商业应用： 治疗帕金森病的新药。