Development of Carvedilol Analogs with Anti-Aggregation Activity for Treating AD

具有抗聚集活性的卡维地洛类似物的开发用于治疗 AD

• 批准号: 8541398
• 负责人: Jun Wang
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541398
• 关键词: Adrenergic Receptor; Adverse effects; Aging; Alzheimer' s Disease; Amyloid; Amyloid Protein AA; Animal Model; Antihypertensive Agents; Attenuated; Binding; Bioavailable; Biochemical; Biological Assay; Biological Availability; Bradycardia; Brain; Cardiovascular system; Chronic; Clinical Trials; Cognitive; Data; Dementia; Deposition; Deterioration; Development; Diagnosis; Disease Progression; Dose; Elderly; Future; Goals; Human; Hypotension; Impaired cognition; In Vitro; Lead; Learning; Libraries; Link; Long-Term Potentiation; Mediating; Methods; Molecular Weight; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome Study; Pathogenesis; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Physiological; Pilot Projects; Population; Post-Traumatic Stress Disorders; Preclinical Drug Evaluation; Prevalence; Preventive; Property; Proteins; Role; Safety; Senile Plaques; Services; Structure-Activity Relationship; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Agents; Time; Transgenic Mice; United States Department of Veterans Affairs; Vertebral column; Veterans; age related; analog; attenuation; base; carvedilol; clinically significant; cognitive function; crosslink; dimer; dosage; extracellular; follow-up; hyperphosphorylated tau; improved; in vivo; mouse model; neuron loss; neuropathology; neurotoxic; neurotransmission; normotensive; novel; pharmacokinetic characteristic; pre-clinical; preclinical efficacy; preclinical study; prevent; public health relevance; receptor binding; restoration; screening; small molecule; tau Proteins; treatment strategy; young adult

DESCRIPTION (provided by applicant): The overall goal of the proposed pilot studies is to confirm the anti-oligomeric activity and reduced 1/2 adrenergic receptor binding activity of carvedilol analogs in vitro, and to further tes their physiological relevance in Alzheimer's disease (AD)-related mechanisms and phenotypes in vivo using TgCRND8 mouse model of AD. Alzheimer's disease is neuropathologically characterized by the accumulation of extracellular plaques composed of ¿-amyloid (A¿) protein, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and loss of neurons. Growing evidence suggests that cognitive deterioration in AD is directly linked to the accumulation of extracellular soluble oligomeric ¿-amyloid (A¿) species rather than amyloid plaque deposition in the brain. Both high molecular weight (HMW) and Low-n A oligomers ranging from dimers to octamers are found in AD brain and have been shown to decrease long-term potentiation (LTP) in mouse models of AD both in vitro and in vivo. These A¿ oligomers are powerful synaptotoxins and thus potential targets for new treatments of AD. In a previous drug screening study, we discovered that carvedilol, a brain bioavailable and bioactive small antihypertensive molecule could significantly attenuate A¿ oligomerization and development of AD-type cognitive deterioration in two experimental transgenic mouse models of AD. However, the potential development of carvedilol for AD is complicated by its cardiovascular activities. Thus we propose to develop molecules with potential anti- A¿ oligomerization effects of carvedilol without its cardiovascular effects. In preliminary screening of small library of carvediol analogs and testing commercially available compounds, we identified 6 bioactive small-molecule compounds that can significantly reduce both low-n oligomer and HMW soluble oligomer formation in vitro. In this application, we propose to further characterize the anti- A¿ oligomeric properties of the 6 lead compounds and their cardiovascular features using diverse in vitro methods and further explore their in vivo translatability in preventing A¿ oligomerization and AD-type cognitive dysfunction using TgCRND8 mouse model of AD. Outcome from these studies will provide critical basis for future follow-up studies exploring the bioavailability and pharmacokinetic characteristics of these lead compounds in animal models and in humans and eventually to an IND-directed pre-clinical safety assessment and Phase I clinical trial.

描述（由申请人提供）： 拟议的试点研究的总体目标是确认抗活性活性，并降低了羊角醇类似物的1/2肾上腺素受体结合活性，并进一步逗弄其在阿尔茨海默氏病（AD）相关的机制和表型中使用TGCRND8小鼠模型的Invivo Invivo在阿尔茨海默氏病中的身体相关性（AD）。阿尔茨海默氏病的神经性特征是由`` - 淀粉样蛋白，淀粉样蛋白，细胞内神经纤维纤维缠结缠结组成的细胞外斑块积累，由热磷酸化的tau蛋白组成的细胞内神经原纤维缠结和NEURON的丧失。越来越多的证据表明，AD的认知恶化直接与细胞外固体寡聚的积累联系在一起，而不是大脑中淀粉样蛋白斑块沉积。在AD大脑中发现了从二聚体到八聚体的高分子量（HMW）和低N A的低聚物，并且已显示出在体外和体内AD的小鼠模型中可以降低长期增强（LTP）。这些寡聚物是强大的突触毒素，因此是新的AD治疗方法的潜在靶标。在先前的药物筛查研究中，我们发现Carvedilol是脑生物利用和生物活性小降压分子可以显着减弱AD的实验性转基因小鼠模型中AD型认知检测的寡聚和发展。但是，Carvedilol的AD的潜在发展是通过其心血管活动编制的。我们建议开发具有卡维地醇的潜在抗A寡聚作用的分子，而没有其心血管效应。在对小雕纤维类似物和市售化合物测试的小库中的初步筛选中，我们确定了6种生物活性的小分子化合物，这些化合物可以显着降低低N寡聚物和HMW固体固体寡聚体的体外形成。在此应用程序中，我们建议进一步表征6种铅化合物的抗A的抗A知识及其心血管特征，并使用潜水员的体外方法来探索其在使用TGCRND8小鼠AD模型的寡聚和AD-TYPE认知功能障碍方面的体内转换性。这些研究的结果将为未来的随访研究提供关键的基础，以探讨动物模型和人类中这些铅化合物的生物利用度和药代动力学特征，并最终进行互联网前临床前安全评估和I期临床试验。