Development of Novel Tricyclic Pyrone Drugs for Treatment of Alzheimer Disease

治疗阿尔茨海默病的新型三环吡喃酮药物的开发

• 批准号: 8681291
• 负责人: Xinmin Simon Xie
• 金额: $ 29.79万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681291
• 关键词: Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein Precursor; Animals; Area; Biological Availability; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Breeding; Calcium; California; Cells; Cessation of life; Chemical Structure; Chemicals; Cholesterol; Chronic; Clinical; Cognition; Cognitive; Collaborations; Data; Dementia; Deposition; Development; Disease; Disease Attributes; Disease Progression; Dose; Drug Formulations; Drug Kinetics; Elderly; Ensure; Evaluation; Event; Excretory function; Functional disorder; Galantamine; Goals; Health; Hippocampus (Brain); Homeostasis; Impaired cognition; Inflammation; Intellectual Property; Investigation; Investigational Drugs; Kansas; Lead; Long-Term Potentiation; Measurable; Measures; Medical; Medicine; Memantine; Memory; Metabolism; Molecular; Motor; Mus; Mutation; Neurodegenerative Disorders; Neurons; Oral; Oral Administration; Organ; Outcome; Outcome Measure; Pathologic; Penetration; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phenotype; Preparation; Preventive; Process; Production; Property; Protein Isoforms; Proteins; Proteolytic Processing; Pyrones; Rattus; Regulatory Affairs; Site; Slice; Small Business Innovation Research Grant; Symptoms; Synapses; System; Technology; Testing; Therapeutic; Therapeutic Studies; Therapeutic Uses; Time; Toxic effect; Toxicology; Translating; Translational Research; Treatment Protocols; Universities; absorption; amyloid peptide; base; chemical synthesis; commercialization; design; donepezil; drug candidate; drug development; drug discovery; efficacy testing; evidence base; excitotoxicity; experience; extracellular; familial Alzheimer disease; improved; in vivo; manufacturing scale-up; neurobehavior; neurobehavioral; neuropathology; neuroprotection; novel; peptide A; phase 1 study; phase 2 study; pre-clinical; preclinical efficacy; presenilin; presenilin-1; public health relevance; rivastigmine; secretase; small molecule; success; therapeutic development; therapy design; trafficking; transgenic model of alzheimer disease

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.

描述（由申请人提供）：用于治疗阿尔茨海默氏病的新型三环吡喃酮药物的开发阿尔茨海默氏病（AD）在全世界范围内折磨着大约3500万人，并且是老年痴呆症的最常见原因。新的AD治疗开发存在未满足的医学需求。淀粉样蛋白-b（Ab）沉积在AD脑已被假设启动级联的分子变化，导致突触功能障碍，炎症，和神经元死亡中观察到的AD脑。因此，设计靶向Ab和下游事件的疗法已成为AD药物开发中的主要努力。本文采用合理设计的方法，合成了一类三环吡喃酮类化合物。先导化合物CP 2和TP 70被发现具有高口服生物利用度、优异的血脑屏障渗透性和低毒性。在“预防性研究”中，向年轻的AD转基因模型口服或腹腔内给予化合物，导致大脑中可溶性和不可溶性抗体种类大幅减少，并保留了记忆和运动功能。此外，我们还发现，除了能够阻断神经元内和细胞外A？聚集体的毒性和形成外，先导TP还增加细胞胆固醇流出，恢复轴突运输，并增强海马突触的平静性。 - 这些协同细胞作用可能是体内效应的潜在机制。这些先导TP化合物的发现来自药物化学家Hua博士、AD神经病理学专家Jin博士和最近的PI Xie博士之间的合作，Xie博士在制药方面拥有丰富的经验，并为CNS治疗领域的药物开发做出了贡献。AfaSci的谢博士首先开发了SmartCageTM系统，然后利用该技术进行转化研究。在本I期SBIR支持下的拟定项目中，我们将通过实现以下具体目标，全面研究先导TP的药代动力学（PK）和体内药效学（PD）：1.在治疗研究中关注两种新型先导化合物CP 2和TP 70：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。我们将重点研究通过口服给药AD模型APP/PS1小鼠的先导化合物的体内疗效（神经行为和神经病理学结果）。这些研究将使用可药物化的PK特征、体内功效（尤其是在认知方面）和改善的治疗效果的标准提供治疗候选物的循证选择。 病理结果。 2.如果需要，使用新的先导化合物LRL 22和LRL 50作为备用化合物，并为所选治疗候选物的良好生产规范（GMP）生产做准备。虽然我们已经鉴定了五种顶级的TP备用化合物，但我们将使用我们先前发现的新的先导化合物LRL 22和LRL 50作为备用化合物，它们具有与TP不同的化学结构，但也显示出对Ab诱导的毒性和神经保护的抑制。如果CP 2和TP 70都不满足治疗候选物的标准，则将重新合成备用化合物并准备如目的1中所述进行体内测试。我们还将优化化学合成工艺，为II期研究确定的候选治疗药物的GMP生产做准备。I期研究的成功将为II期项目中的研究性新药（IND）研究做好准备。我们的最终目标是将我们对新型TP化合物的临床前发现转化为具有AD疾病修饰特性的临床治疗候选物。