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: 9348491
• 负责人: Xinmin Simon Xie
• 金额: $ 97.31万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348491
• 关键词: APP-PS1; Adverse effects; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; 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); 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; Methods; Modeling; Molecular; Motor; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Oral; Oral Administration; Outcome; Pathologic; Pathology; Penetration; Peptide Metabolism; 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; 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; peptide B; phase 1 study; programs; protein biomarkers; receptor function; rivastigmine; success; targeted treatment; tau Proteins; 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- (A) 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 A 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 A 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 A 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-A 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 A, Aplaque 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. 项目总结/摘要 阿尔茨海默氏病 (AD) 困扰着全球约 4400 万人，是导致以下疾病的最常见原因 老年人痴呆症。新阿尔茨海默病的发展存在未满足的医疗需求 疗法。据推测，沉积在阿尔茨海默病大脑中的淀粉样蛋白 - (A) 会启动 导致突触功能障碍、炎症和神经元死亡的分子级联变化。所以， 设计针对 A 和下游事件的疗法已成为阿尔茨海默病的主要策略 药物开发。我们采取合理的设计方法，合成了一类三环吡喃酮 化合物 (TP) 表现出有效的细胞保护作用，抵抗 A 毒性。 在我们已完成的 SBIR 一期项目中，发现先导化合物 CP2 和 TP70 具有较高的口服活性。 生物利用度高、血脑屏障通透性好、毒性低。口服给予化合物 在一项“预防性试验”中，年轻的阿尔茨海默病转基因小鼠模型的结果显着降低 大脑中可溶性和不可溶性 A 物种，并保留记忆和运动功能。此外，我们还有 发现先导 TP 减少了神经元内和细胞外 Aβ 聚集以及 过度磷酸化 tau (p-tau)、恢复轴突运输和调节海马突触 NMDA 介导的活性和可塑性——这些多重协同细胞作用，而不是抗 A 毒性 单独而言，可能是其体内作用的潜在机制。 在这个拟议的 SBIR 第二阶段项目中，我们最初的第一阶段调查团队在啮齿动物方面拥有额外的专业知识 脑成像、临床阿尔茨海默病治疗和非 GLP 毒性研究提供者将进行 上述两种 TP 的药代动力学和药效学 (PK/PD) 纵向研究 分子在新的阿尔茨海默病转基因大鼠模型中，以选择最佳先导化合物作为 IND 候选人。我们现在选择新的 TgF344-AD 大鼠模型进行研究，因为它们表现出 寡聚 A、A 斑块形成​​、Tau 病理学、行为损伤和神经元损失，忠实地 概括了人类阿尔茨海默病的特征。我们将通过完成以下任务来实现我们的目标 具体目标： 1. 使用我们建立的测定/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、血浆和脑脊液浓度、代谢物鉴定、P450 抑制/诱导，以及 排泄。将检查体内功效，尤其是认知、脑成像和病理结果 以及脑脊液和大脑中的 Aβ 和 tau 蛋白生物标志物，与 PD 结局相关。 2. IND支持研究的准备。对以下药物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者，以帮助做出是否继续 在 SBIR IIB 期或其他项目的竞争性更新中做出 IND 支持研究的决定。 3. 探索CP2和TP70​​在转基因大鼠模型中的作用机制 阿尔茨海默病。我们将研究 CP2 和 TP70 对海马突触的调节，特别是 NMDA 受体介导的突触活性、可塑性和突触外 NMDA 受体介导 活动，并探索它们与其他分子和细胞活动的联系 第二阶段的成功将产生 IND 候选药物。一旦提交 IND 申请，将会吸引 非政府支持和制药合作伙伴对该新型候选药物的临床开发 用于治疗阿尔茨海默病。