SYNTHETIC SOD/CATALASE MIMICS FOR STROKE

合成 SOD/过氧化氢酶模拟物治疗中风

• 批准号: 6386923
• 负责人: SUSAN DOCTROW
• 金额: $ 46.28万
• 依托单位: EUKARION, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6386923
• 关键词: antioxidants; biomimetics; catalase; chemical property; drug design /synthesis /production; drug screening /evaluation; enzyme activity; free radical oxygen; laboratory rat; manganese; nerve injury; oxidative stress; solubility; stroke; superoxide dismutase; synthetic enzyme

Stroke is the third leading cause of death in the United States and is considered to be the most common cause of adult disability. Pharmacological intervention has made little, if any, impact in preventing neurological damage that occurs during the hours and days following stroke onset. Reactive oxygen species (ROS) are strongly implicated in this damage. Eukarion has developed a series of low molecular weight synthetic compounds that are catalytic ROS scavengers, mimicking the antioxidants superoxide dismutase (SOD) and catalase, and are highly protective in rodent stroke models. This SBIR project will investigate the potential therapeutic value of these SOD/catalase mimics in stroke. During Phase I, several of the compounds were evaluated for their neuroprotective activity in the rodent stroke model, and for other relevant properties such as solubility and stability. Based on this research three compounds were selected as candidate molecules for preclinical and clinical development. Research proposed for Phase II will involve: (l) Safety screening studies to enable selection of one compound as the lead molecule ("EUK-n"); (2) Development of an injectable formulation for clinical administration of EUK-n; (3) Formal toxicity studies; and (4) Pharmacokinetic and biodistribution studies. This will provide necessary information to file an Investigational New Drug application with the FDA in order to initiate clinical trials with EUK-n. PROPOSED COMMERCIAL APPLICATION: Stroke affects about 500,000 patients annually in the U.S. and there is no satisfactory treatment to prevent the neurological darn age that results. Eukarion's novel SOD/catalase mimics are highly neuroprotective in rodent stroke models. This SBIR research will provide key preclinical information that will enable Eukarion to apply to the FDA for permission to initiate clinical trials with an SOD/catalase mimic.

中风是美国第三大死亡原因，被认为是成人残疾的最常见原因。药物干预对于预防中风发作后数小时和数天内发生的神经损伤几乎没有作用（如果有的话）。活性氧 (ROS) 与这种损害密切相关。 Eukarion 开发了一系列低分子量合成化合物，这些化合物是催化 ROS 清除剂，模仿抗氧化剂超氧化物歧化酶 (SOD) 和过氧化氢酶，对啮齿动物中风模型具有高度保护作用。该 SBIR 项目将研究这些 SOD/过氧化氢酶模拟物在中风中的潜在治疗价值。在第一阶段，评估了几种化合物在啮齿动物中风模型中的神经保护活性，以及​​其他相关特性，例如溶解度和稳定性。基于这项研究，选择了三种化合物作为临床前和临床开发的候选分子。拟议的第二阶段研究将包括： (l) 安全筛选研究，以选择一种化合物作为先导分子（“EUK-n”）； (2) 开发用于EUK-n临床给药的注射剂型； (3) 正式的毒性研究； (4) 药代动力学和生物分布研究。这将为向 FDA 提交研究性新药申请提供必要的信息，以便启动 EUK-n 的临床试验。拟议的商业应用：在美国，中风每年影响大约 500,000 名患者，并且没有令人满意的治疗方法来预防由此导致的神经老化。 Eukarion 的新型 SOD/过氧化氢酶模拟物在啮齿动物中风模型中具有高度神经保护作用。这项 SBIR 研究将提供关键的临床前信息，使 Eukarion 能够向 FDA 申请启动 SOD/过氧化氢酶模拟物的临床试验。