Development of patented tricyclic pyrones molecules for the treatment of Alzheimer’s Disease

开发用于治疗阿尔茨海默病的专利三环吡喃酮分子

• 批准号: 9442675
• 负责人: Xinmin Simon Xie
• 金额: $ 96.07万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2021-02-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9442675
• 关键词: APP-PS1; Adverse effects; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Binding Proteins; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain imaging; Calcium; California; Chronic; Clinical; Cognition; Collaborations; Contract Services; Cytochrome P450; Cytoprotection; Dementia; Deposition; Development; Disease; Drug Kinetics; Early treatment; Elderly; Electrophysiology (science); Event; Excitatory Postsynaptic Potentials; Excretory function; Exhibits; Functional disorder; Galantamine; Goals; Grant; Health; Hepatocyte; Hippocampus (Brain); Homeostasis; Human; Image; Impairment; Inflammation; Investigation; Investigational Drugs; Investigational New Drug Application; Joints; Kansas; Lead; Learning; Legal patent; Link; Long-Term Potentiation; Longitudinal Studies; Mediating; Medical; Memantine; Memory; Memory impairment; Metabolism; Methods; Modeling; Molecular; Motor; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Oral; Oral Administration; Outcome; Pathologic; Pathology; Penetration; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Plasma; Population; Preparation; Preventive; Provider; Pyrones; Rattus; Rodent; Safety; Site; Slice; Small Business Innovation Research Grant; Symptoms; Synapses; Techniques; Testing; Therapeutic; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; Universities; abeta oligomer; abeta toxicity; base; behavior test; behavioral impairment; brain tissue; clinical development; design; donepezil; drug candidate; drug development; drug metabolism; excitotoxicity; extracellular; hyperphosphorylated tau; in vivo; insight; intraneuronal beta amyloid; mouse model; neuron loss; neuroprotection; neurotransmission; novel; novel therapeutics; phase 1 study; programs; protein biomarkers; receptor function; rivastigmine; service organization; success; targeted treatment; tau Proteins; tau-1; therapeutic candidate; therapy design; trafficking; treatment trial

7. Project Summary/Abstract Alzheimer’s disease (AD) afflicts approximately 44 million people worldwide and is the most common cause of dementia in the elderly. There is an unmet medical need for the development of new Alzheimer’s disease therapeutics. Amyloid-β (Aβ) deposited in the Alzheimer’s diseased brain has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death. Therefore, designing therapies targeting Aβ and downstream events have become major strategies in Alzheimer’s disease drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone compounds (TPs) that show potent cell protection against Aβ toxicity. In our completed SBIR Phase I project, the lead compounds CP2 and TP70 were found to have high oral bioavailability, excellent blood–brain barrier permeability, and low toxicity. Administering compounds orally to young Alzheimer’s disease transgenic mouse models in a “preventive trial” resulted in substantially reduced soluble and insoluble Aβ species in the brain and preserved memory and motor function. Furthermore, we have found that the lead TPs decreased both intraneuronal and extracellular Aβ aggregates as well as hyperphosphorylated tau (p-tau), restored axonal trafficking, and modulated hippocampal synaptic NMDA-mediated activity and plasticity — these multiple synergistic cellular actions, rather than anti-Aβ toxicity alone, could be potential mechanisms underlying their in vivo effects. In this proposed SBIR Phase II project, our original Phase I investigative team with additional expertise in rodent brain imaging, clinical Alzheimer’s disease treatments, and non-GLP toxicity study providers, will conduct longitudinal studies of pharmacokinetics and pharmacodynamics (PK/PD) on the two aforementioned TP molecules in a new transgenic rat model of Alzheimer’s disease, in order to select the best lead as the IND candidate. We now choose the new TgF344-AD rat model for our studies because they exhibit accumulation of oligomeric Aβ, Aβplaque formation, Tau pathology, behavioral Impairment, and neuronal loss that faithfully recapitulate hallmarks of human Alzheimer’s disease. We will achieve our goal by accomplishing the following Specific Aims: 1. Conduct PK/PD studies of CP2 and TP70 on TgF344-AD rats using our established assays/tests. The drug metabolism and PK studies include plasma and hepatocyte stability, plasma and brain protein binding, plasma and CSF concentrations, metabolite identification, P450 inhibition/induction, and excretion. In vivo efficacy especially cognition, brain imaging, and pathologic outcomes will be examined along with Aβ and tau protein biomarkers in CSF and brain to correlate with PD outcomes. 2. Preparation for IND-enabling studies. Conduct pilot safety pharmacology and non-GLP toxicology on the selected therapeutic candidates through contract service organizations to help make a go/no-go decision for IND-enabling studies in a Competing Renewal of SBIR Phase IIB or other programs. 3. Explore mechanisms of action underlying CP2 and TP70 efficacy in the transgenic rat model of Alzheimer disease. We will investigate CP2 and TP70 modulation of hippocampal synaptic, particularly NMDA receptor-mediated synaptic activity, plasticity and extrasynaptic NMDA receptors-mediated activity, and explore their links to other molecular and cellular actions Success in Phase II will lead to an IND candidate. Once an IND application is filed, it will attract non-government support and pharmaceutical partners for clinical development of this novel drug candidate for the treatment of Alzheimer’s disease.

7。项目摘要/摘要 阿尔茨海默氏病（AD）在全球范围内约有4400万人 对新阿尔茨海默氏病的发展有未满足的医疗需求 疗法。假设沉积在阿尔茨海默氏症脑中的淀粉样蛋白β（Aβ）已被认为启动A 一系列分子变化导致突触功能障碍，注射和神经元死亡。所以， 设计针对Aβ和下游事件的疗法已成为阿尔茨海默氏病的主要策略 药物开发。我们采取了一种理性的设计方法，并合成了一类三轮车pyrone 表现出对Aβ毒性的潜在细胞保护的化合物（TPS）。 在我们完成的SBIR I阶段项目中，发现铅化合物CP2和TP70​​具有高口服 生物利用度，出色的血脑屏障渗透性和低毒性。口服化合物 在“预防试验”中，年轻的阿尔茨海默氏病转基因小鼠模型大大减少了 可溶性和不溶性Aβ物种在大脑中，保留记忆和运动功能。此外，我们还有 发现铅TPS降低了神经内神经元和细胞外Aβ聚集体以及 高磷酸化的tau（p-tau），恢复的轴突运输和调节海马突触 NMDA介导的活性和可塑性 - 这些多种协同的细胞作用，而不是抗Aβ的毒性 仅凭其体内效应的潜在机制可能是潜在的机制。 在这个拟议的SBIR II期项目中，我们的原始I期调查团队拥有啮齿动物的其他专家 大脑成像，临床阿尔茨海默氏病治疗和非GLP毒性研究提供者将进行 两种关于TP的药代动力学和药效学（PK/PD）的纵向研究（PK/PD） 为了选择最佳铅作为IND 候选人。现在，我们为我们的研究选择新的TGF344-AD大鼠模型，因为它们暴露了 寡聚Aβ，AβPlaquque形成，TAU病理学，行为障碍和神经元丧失，忠实地 概括了人类阿尔茨海默氏病的标志。我们将通过完成以下内容来实现我们的目标 具体目的： 1。使用我们已建立的测定/测试对TGF344-AD大鼠进行CP2和TP70​​的PK/PD研究。 药物代谢和PK研究包括血浆和肝细胞稳定性，血浆和脑蛋白 结合，血浆和CSF浓度，代谢物鉴定，P450抑制/诱导以及 排泄。将检查体内效率，尤其是认知，脑成像和病理结局 CSF和大脑中的Aβ和TAU蛋白生物标志物与PD结局相关。 2。准备辅助研究。在进行试点安全药理学和非GLP毒理学 通过合同服务组织选定的治疗候选人，以帮助您进行/不进行 在SBIR IIB或其他计划的竞争更新中进行辅助研究的决定。 3。探索CP2和TP70​​效率的作用机理的转基因大鼠模型 阿尔茨海默氏病。我们将研究海马突触的CP2和TP70​​调制，特别是 NMDA受体介导的合成活性，可塑性和外部NMDA受体介导的 活动，并探索它们与其他分子和细胞作用的联系 第二阶段的成功将导致IND候选人。一旦提交IND申请，它将吸引 这位新型药物的临床开发的非政府支持和药物伙伴 治疗阿尔茨海默氏病。