Development of Novel Tricyclic Pyrone Drugs for Treatment of Alzheimer Disease

描述(申请人提供)：开发治疗阿尔茨海默病的新型三环吡喃酮类药物阿尔茨海默病(AD)困扰着全球约3500万人，是导致老年人痴呆的最常见原因。有一个新的AD治疗开发的医学需求尚未得到满足。沉积在AD脑中的淀粉样蛋白b(Ab)被认为启动了一系列分子变化，导致AD脑中观察到的突触功能障碍、炎症和神经元死亡。因此，设计针对抗体及其下游事件的治疗方法已成为AD药物开发的主要努力。我们采用合理的设计方法合成了一类三环吡喃酮类化合物(TPS)。先导化合物CP2和TP70被发现具有较高的口服生物利用度、良好的血脑屏障通透性和低毒性。在“预防性研究”中，对年轻的AD转基因模型进行口服或腹腔注射化合物，可显著减少大脑中可溶和不可溶的抗体种类，并保留记忆和运动功能。此外，我们还发现，除了能够阻断神经元内和细胞外聚集的毒性和形成，铅TPS还增加细胞胆固醇外流，恢复轴突运输，并增强海马区突触的平稳性 -这些协同的细胞作用可能是体内效应的潜在机制。这些TP先导化合物的发现来自于药物化学家华博士、AD神经病理专家金博士以及最近在药物方面拥有丰富经验并为中枢神经系统治疗领域的药物开发做出贡献的谢博士的合作。AfaSci的谢博士从开发SmartCageTM系统开始，然后在翻译研究中利用了这项技术。在第一阶段SBIR的支持下，我们将深入研究铅TPS的药代动力学(PK)和体内药效学(PD)，实现以下具体目标：1.在治疗研究中，重点研究两种新的先导化合物CP2和TP70：我们将生成先导化合物的PK/PD和ADME(吸收、分布、代谢和排泄)曲线。我们将重点研究口服铅化合物对AD模型APP/PS1小鼠的体内疗效(神经行为和神经病理结果)。这些研究将根据可用药的PK概况、体内疗效，特别是在认知方面的疗效和改善的标准，为治疗候选者提供循证选择。 病理结果。2.如果需要，使用新型先导化合物LRL22和LRL50作为后备化合物，并为所选候选治疗药物的良好制造规范(GMP)生产做准备。虽然我们已经确定了五个顶级的备用TP化合物，但我们将使用我们之前发现的新的先导LRL22和LRL50作为备用化合物，它们具有不同于TP的化学结构，但也显示出抑制抗体诱导的毒性和神经保护的作用。如果CP2和TP70都不符合候选治疗的标准，备用化合物将被重新合成，并准备好在体内进行测试，如目标1所述。我们还将优化化学合成过程，为第二阶段研究确定的候选治疗药物生产GMP做准备。第一阶段研究的成功将为第二阶段项目中的研究性新药(IND)研究做准备。我们的最终目标是将我们在临床前发现的新型TP化合物转化为具有AD疾病修改特性的临床候选治疗药物。

DESCRIPTION (provided by applicant): Development of Novel Tricyclic Pyrone Drugs for Treatment of Alzheimer's Disease Alzheimer's disease (AD) afflicts approximately 35 million people worldwide and is the most common cause of dementia in the elderly. There is an unmet medical need for new AD therapeutic development. Amyloid-b (Ab) deposited in AD brains has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death observed in AD brains. Therefore, designing therapies targeting Ab and downstream events have become a major effort in AD drug development. We have taken the rational design approach and synthesized a class of tricyclic pyrone compounds (TPs). The lead compounds CP2 and TP70 were found to have high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity. Administering compounds either orally or intraperitoneally to young AD transgenic models in 'preventive studies' resulted in substantially reduced soluble and insoluble Ab species in the brain and preserved memory and motor function. Furthermore, we have found that in addition to being able to block the toxicity and formation of both intraneuronal and extracellular A¿ aggregates, the lead TPs also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic placidity - these synergistic cellular actions could be potential mechanisms underlying in vivo effects. The discovery of these lead TP compounds comes from the collaboration among Dr. Hua, a medicinal chemist, Dr. Jin, an AD neuropathology expert, and recently the PI Dr. Xie, who has substantial experience in pharmaceuticals and contributed to drug development in the CNS therapeutic area. Dr. Xie at AfaSci started with developing the SmartCageTM system and then has taken advantage of the technology in translational research. In the proposed project with the support of this phase I SBIR, we will thoroughly study pharmacokinetics (PK) and in vivo pharmacodynamics (PD) of the lead TPs, through accomplishment of the following Specific Aims: 1. Focus on two novel lead compounds CP2 and TP70 in the therapeutic studies: We will generate PK/PD and ADME (absorption, distribution, metabolism, and excretion) profiles of lead compounds. We will focus on investigating the in vivo efficacy (neurobehavioral and neuropathological outcomes) of lead compounds by oral administration to the AD model APP/PS1 mice. These studies will provide evidence-based selection of a therapeutic candidate using the criteria of druggable PK profile, in vivo efficacy especially in cognition, and improved pathologic outcomes. 2. Utilization of novel lead compounds LRL22 and LRL50 as backup compounds, if needed, and preparation for good manufacturing practice (GMP) production of the selected therapeutic candidate. Although we have identified five top backup TP compounds, we will use our previously discovered novel leads LRL22 and LRL50 which possess different chemical structures from TP, but also shown inhibition of Ab-induced toxicity and neuroprotection as backup compounds. The backup compounds will be re-synthesized and ready to be tested in vivo as described in Aim 1, should both CP2 and TP70 not fulfill the criteria of therapeutic candidates. We will also optimize the chemical synthesis process in preparation for GMP production of the identified therapeutic candidate for a Phase II study. Success in the Phase I study will prepare for investigational new drug (IND)-enabling studies in a Phase II project. Our ultimate goal is to translate our preclinical discovery of the novel TP compounds into clinical therapeutic candidates that possess AD disease-modifying properties.