SOD/Catalase mimics for age-related learning impairment

SOD/过氧化氢酶模拟物治疗与年龄相关的学习障碍

• 批准号: 6934779
• 负责人: SUSAN DOCTROW
• 金额: $ 72.06万
• 依托单位: PROTEOME SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934779
• 关键词: aging; animal old age; behavioral /social science research tag; brain disorder chemotherapy; catalase; chemoprevention; cognition disorders; dosage; drug administration rate /duration; drug design /synthesis /production; drug screening /evaluation; enzyme activity; high performance liquid chromatography; immunocytochemistry; laboratory mouse; laboratory rat; learning disorders; liquid chromatography mass spectrometry; neurotoxicology; nonhuman therapy evaluation; oxidative stress; pharmacokinetics; superoxide dismutase

DESCRIPTION (provided by applicant): Aging is often accompanied by a deterioration of learning and memory processes, a condition now referred to as mild cognitive impairment (MCI). Recent studies have indicated that 12% of patients afflicted with MCI will develop Alzheimer's disease, as opposed to 2% of the general population. Although the causes underlying MCI are not known, there is much evidence implicating oxidative damage. Eukarion has developed a class of low molecular weight molecules that are catalytic scavengers of reactive oxygen species (ROS), acting as mimics for the endogenous antioxidant enzymes superoxide dismutase (SOD) and catalase. These compounds are effective in many models for neurological and other classes of diseases. During Phase I of this STTR grant, two of these compounds, EUK-189 and EUK-207, were tested for their activity in preventing age-related loss of cognitive function and accumulation of oxidative stress in mice of early middle age" (8 to 11 months). Both improved cognitive performance and reduced several indicators of oxidative stress in the brain. These Phase I data support further investigation of these compounds as therapeutic agents for MCI and, potentially, for age-related neurodegenerative disease in humans. Phase II research will focus on further testing the two compounds in age-related loss of cognitive performance and on conducting key preclinical research to select one for more advanced preclinical research leading to an Investigational New Drug (IND) application for a chronic neurodegenerative disorder. Specific aims will (1) produce scale-up batches of both compounds under "near-GMP: conditions; in mice, test effects of long-term dosing, and lower doses, of compounds on (2) cognitive impairment, (3) brain oxidative stress, (4) drug and Mn levels, and (5) toxicology assessments; and (6) investigate potential chronic dosing methods for use in the clinic. (7) Based on these data, a lead compound will be selected toward the end of Phase II, and formal preclinical work will commence.

描述(申请人提供)：衰老通常伴随着学习和记忆过程的恶化，这种情况现在被称为轻度认知障碍(MCI)。最近的研究表明，患有MCI的患者中有12%会患上阿尔茨海默氏症，而普通人群中的这一比例为2%。尽管MCI的潜在原因尚不清楚，但有许多证据表明氧化损伤有关。Eukarion开发了一类小分子，它们是活性氧自由基(ROS)的催化清除剂，充当内源抗氧化酶超氧化物歧化酶(SOD)和过氧化氢酶(CAT)的模拟物。这些化合物对神经系统和其他类型的疾病的许多模型都有效。在这项STTR赠款的第一阶段，对其中两种化合物EUK-189和EUK-207进行了活性测试，以防止与年龄相关的认知功能丧失和中年早期(8至11个月)小鼠氧化应激的积累。两者都改善了认知能力，并减少了大脑中氧化应激的几个指标。这些第一阶段的数据支持进一步研究这些化合物作为治疗MCI的药物，并潜在地治疗人类与年龄相关的神经退行性疾病。第二阶段的研究将集中于进一步测试这两种化合物在与年龄相关的认知能力丧失方面的作用，并进行关键的临床前研究，以选择一种用于更先进的临床前研究，从而将研究性新药(IND)应用于一种慢性神经退行性疾病。具体目标将：(1)在“接近GMP：”的条件下生产这两种化合物的放大批次；(3)在小鼠身上测试长期服用化合物和较低剂量化合物对(2)认知损害、(3)大脑氧化应激、(4)药物和锰水平以及(5)毒理学评估的影响；(6)研究可能用于临床的慢性给药方法。(7)基于这些数据，将在第二阶段结束时选择一种先导化合物，并开始正式的临床前工作。