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

7.项目总结/摘要 阿尔茨海默病（AD）困扰着全世界约4400万人，并且是阿尔茨海默病最常见的病因。 老年痴呆症有一个未满足的医疗需求的发展新的阿尔茨海默氏病 治疗学淀粉样蛋白（A β）沉积在阿尔茨海默氏病的大脑中，被假设为启动了一种新的疾病。 导致突触功能障碍、炎症和神经元死亡的分子变化级联。因此，我们认为， 设计针对阿尔茨海默病及其下游事件的治疗方法已成为阿尔茨海默病的主要策略 药物开发我们采用合理的设计方法，合成了一类三环吡喃酮 这些化合物（TP）显示出有效的细胞保护作用以对抗A β毒性。 在我们完成的SBIR第一阶段项目中，发现先导化合物CP 2和TP 70具有高的口服活性。 生物利用度、优异的血脑屏障渗透性和低毒性。将化合物口服给药至 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 可溶性和不溶性的A类物质在大脑中，并保存记忆和运动功能。此外，我们有 发现，铅TP减少神经元内和细胞外Aβ聚集， 过度磷酸化的tau蛋白（p-tau），恢复轴突运输，调节海马突触 NMDA介导的活性和可塑性-这些多个协同细胞作用，而不是抗A β毒性 可能是其体内效应的潜在机制。 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小组拥有啮齿动物方面的额外专业知识， 脑成像，临床阿尔茨海默病治疗和非GLP毒性研究提供商，将进行 上述两种TP的药代动力学和药效学（PK/PD）纵向研究 分子在一种新的阿尔茨海默病转基因大鼠模型，以选择最好的铅作为IND 候选人我们现在选择新的TgF 344-AD大鼠模型用于我们的研究，因为它们表现出累积的 寡聚腺苷酸、腺苷酸斑块形成、Tau病理学、行为障碍和神经元损失， 概括了人类阿尔茨海默病的特征。我们将通过以下方式实现我们的目标 具体目标： 1.使用我们已建立的测定/试验在TgF 344-AD大鼠中进行CP 2和TP 70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、代谢物鉴别、P450抑制/诱导，以及 排泄将检查体内疗效，特别是认知、脑成像和病理结果 沿着CSF和脑中的Aβ和tau蛋白生物标志物与PD结局相关。 2.为国家自主研发能力研究做准备。进行安全药理学和非GLP毒理学试验， 通过合同服务组织选定的治疗候选人，以帮助确定是否可行 决定在SBIR IIB期或其他项目的竞争性更新中进行IND使能研究。 3.探索CP 2和TP 70在转基因大鼠模型中的作用机制。 老年痴呆症我们将研究CP 2和TP 70对海马突触的调节，特别是对海马神经元突触的调节。 NMDA受体介导的突触活动、可塑性和突触外NMDA受体介导的突触突触后突触的可塑性 活性，并探索它们与其他分子和细胞活动的联系 第二阶段的成功将导致IND候选人。一旦提交IND申请， 非政府支持和制药合作伙伴对这种新型候选药物的临床开发 用于治疗老年痴呆症

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.