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）： 拟议试点研究的总体目标是在体外确认卡维地洛类似物的抗寡聚活性和降低 1/2 肾上腺素能受体结合活性，并进一步测试其在阿尔茨海默病 (AD) 相关机制和表型中的生理相关性。使用 TgCRND8 体内 AD 小鼠模型的神经病理学特征是由 ¿淀粉样蛋白 (A¿)、由过度磷酸化 tau 蛋白组成的细胞内神经原纤维缠结以及神经元损失。越来越多的证据表明，AD 中的认知功能恶化与细胞外可溶性寡聚体的积累直接相关。 AD 大脑中发现了高分子量 (HMW) 和低 n A 寡聚体（从二聚体到八聚体），并且已被证明可以降低长时程增强作用。 LTP）在体外和体内 AD 小鼠模型中的应用。寡聚物是强大的突触毒素，因此是 AD 新疗法的潜在靶标。在之前的药物筛选研究中，我们发现卡维地洛（一种大脑生物利用度和生物活性的小抗高血压分子）可以显着减弱 A¿然而，卡维地洛治疗 AD 的潜在发展因其心血管活性而变得复杂，因此我们建议开发具有潜在抗 A 的分子。在卡维地洛类似物小型库的初步筛选和市售化合物的测试中，我们鉴定了 6 种生物活性小分子化合物，它们可以在体外显着减少低 n 寡聚物和 HMW 可溶性寡聚物的形成。应用中，我们建议进一步表征抗A¿使用不同的体外方法研究 6 种先导化合物的寡聚特性及其心血管特征，并进一步探索它们在预防 A¿使用 AD 的 TgCRND8 小鼠模型进行寡聚化和 AD 型认知功能障碍，这些研究的结果将为探索这些先导化合物在动物模型和人类中的生物利用度和药代动力学特征以及最终的 IND 提供重要基础。指导临床前安全性评估和I期临床试验。