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

7.项目摘要/摘要 阿尔茨海默病(AD)困扰着全球约4400万人，是导致老年痴呆症的最常见原因 老年痴呆症。新的阿尔茨海默病的发展有一个未得到满足的医学需求 治疗学。淀粉样蛋白-β(A-β)沉积在阿尔茨海默病患者的大脑中，被假设为启动了一种 一连串的分子变化导致突触功能障碍、炎症和神经元死亡。因此， 设计针对Aβ和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。我们采取了合理的设计方法，合成了一类三环吡喃酮 化合物(TP)对Aβ毒性具有强大的细胞保护作用。 在我们完成的SBIR第一阶段项目中，发现先导化合物CP2和TP70具有较高的口服量 生物利用度高，血脑屏障通透性好，毒性低。口服复方制剂给药 年轻的阿尔茨海默病转基因小鼠模型在一项“预防性试验”中的结果是显著减少 可溶的和不可溶的：大脑中的一种β，能保护记忆和运动功能。此外，我们还拥有 发现铅可使神经元内和细胞外的Aβ聚集体减少，以及 过度磷酸化tau(p-tau)、恢复轴突运输和调制海马突触 N-甲基-D-天冬氨酸介导的活性和可塑性--这些多重协同作用，而不是抗A-β毒性 单独来说，可能是它们在体内影响的潜在机制。 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拥有额外的啮齿动物专业知识 脑成像、阿尔茨海默病临床治疗和非GLP毒性研究提供者将进行 两种茶多酚的药代动力学和药效学(PK/PD)纵向研究 一种新的阿尔茨海默病转基因大鼠模型中的分子，以选择最佳的铅作为IND 候选人。我们现在选择新的TgF344-AD大鼠模型进行研究，因为它们显示出 寡聚体Aβ、Aβ斑块形成、Tau病理、行为损害和神经元丢失 概括了人类阿尔茨海默病的特征。我们将通过做好以下工作来实现我们的目标 具体目标： 1.在TgF344-AD大鼠上进行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 排泄物。将检查体内疗效，特别是认知、脑成像和病理结果。 脑脊液和脑组织中的A、β和tau蛋白生物标志物与帕金森病预后相关。 2.为促进可持续发展的研究做准备。开展安全药理学和非GLP毒理学试点 通过合同服务组织选择的治疗对象帮助进行/不进行 在SBIR第二阶段B或其他计划的竞争性续签中决定支持IND的研究。 3.探讨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对海马区突触的调节，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 活性，并探索它们与其他分子和细胞活动的联系 在第二阶段的成功将导致IND候选人。一旦IND申请被提交，它将吸引 非政府支持和制药合作伙伴为这种新药的临床开发提供支持 用于治疗阿尔茨海默氏症。

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-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.