PARP Inhibitors for Treating Cardiac Arrest

PARP 抑制剂治疗心脏骤停

• 批准号: 6739834
• 负责人: JIE ZHANG
• 金额: $ 9.5万
• 依托单位: GUILFORD PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739834
• 关键词: cardiovascular disorder chemotherapy; dosage; drug design /synthesis /production; drug screening /evaluation; electroencephalography; enzyme inhibitors; heart arrest; histology; laboratory rat; nervous system disorder chemotherapy; neuropharmacology; neuroprotectants; nonhuman therapy evaluation; pentosyltransferase; pharmacokinetics; toxicology; voltage /patch clamp

DESCRIPTION (provided by applicant): The objective for the proposed study is to determine the feasibility of using novel small molecule poly (ADP-ribose) polymerase (PARP) inhibitors as neuroprotective and cardioprotective agents to treat cardiac arrest patients for increased survival rate with improving prognosis in neurological and cardiac functions. Energy depletion due to over-activation of PARP has been found to cause neuronal and myocardial cell death during ischemia and reperfusion injuries. Inhibition of PARP, either by pharmacological inhibitors or gene deletion, has been proved an effective way to reduce infarct volumes in animal models of cerebral ischemia as well as regional heart ischemia. Guilford Pharmaceuticals Inc. has identified a series of water soluble PARP inhibitors that 1) achieved high level accumulation in plasma, heart and brain after intravenous dosing and 2) provided neuroprotection and cardioprotection in rat models of stroke and heart ischemia. We intend to test our proprietary PARP inhibitors in a well-established rat model of cardiac arrest. In collaboration with Dr. Daniel Hanley (the Johns Hopkins School of Medicine), we demonstrated that our leading PARP inhibitor, GPI 15427 significantly increased the survival rate with improved speed of recovery and neurological scores. To achieve the objective of the current study, we have designed a series of experiments that are aimed at 1) optimizing the chemical properties of GPI 15427 series compounds for "drug like" properties; 2) characterizing the pharmacokinetic and toxicological profiles of GPI 15427 for better dosing regimen; and 3) determine the optimal dose-effect relationship of GPI 15427 series compounds in a rat model of cardiac arrest. We expect results from this phase I study will yield information for assessing the prospect of a phase II preclinical development towards clinical trials and commercialization of PARP inhibitors to treat cardiac arrest patients.

描述（由申请人提供）：拟议研究的目的是确定使用新型小分子聚（ADP-核糖）聚合酶（PARP）抑制剂作为神经保护剂和心脏保护剂来治疗心脏骤停患者以提高生存率并改善生存率的可行性。神经和心脏功能的预后。研究发现，由于 PARP 过度激活导致的能量消耗会在缺血和再灌注损伤期间导致神经元和心肌细胞死亡。通过药物抑制剂或基因删除来抑制 PARP 已被证明是减少脑缺血和局部心脏缺血动物模型中梗塞体积的有效方法。 Guilford Pharmaceuticals Inc. 已鉴定出一系列水溶性 PARP 抑制剂，1) 静脉给药后在血浆、心脏和大脑中实现高水平积累，2) 在中风和心脏缺血的大鼠模型中提供神经保护和心脏保护。我们打算在成熟的心脏骤停大鼠模型中测试我们专有的 PARP 抑制剂。我们与 Daniel Hanley 博士（约翰霍普金斯大学医学院）合作，证明了我们领先的 PARP 抑制剂 GPI 15427 显着提高了存活率，改善了恢复速度和神经评分。为了实现本研究的目的，我们设计了一系列实验，旨在1）优化GPI 15427系列化合物的化学性质，使其具有“类药”性质； 2) 表征 GPI 15427 的药代动力学和毒理学特征，以获得更好的给药方案； 3)确定GPI 15427系列化合物在心脏骤停大鼠模型中的最佳量效关系。我们预计这一 I 期研究的结果将提供信息，用于评估 PARP 抑制剂治疗心脏骤停患者的临床试验和商业化 II 期临床前开发的前景。