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

基本信息

批准号：
8516617
负责人：
Xinmin Simon Xie
金额：
$ 29.81万
依托单位：
AFASCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516617
关键词：
Adverse effects Affect Alzheimer&apos s Disease Alzheimer&apos 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 Peptide Synthesis Peptides 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 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 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

项目摘要

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（由适用提供）：开发新型的三环吡啶药物用于治疗阿尔茨海默氏病阿尔茨海默氏病（AD），全世界约有3500万人，是最古老的痴呆症最常见的原因。对新的AD治疗开发有未满足的医疗需求。假设沉积在AD大脑中的淀粉样蛋白B（AB）启动了一系列分子变化，导致在AD大脑中观察到突触功能障碍，感染和神经元死亡。因此，设计针对AB和下游事件的疗法已成为AD药物开发的主要努力。我们采用了合理的设计方法，并合成了一类三环吡喃化合物（TPS）。发现铅化合物CP2和TP70具有高口服生物利用度，出色的血脑屏障渗透性和低毒性。在“预防性研究”中，口服或腹膜内的化合物对年轻的AD转基因模型产生了大幅度降低的大脑中的固体和不溶性AB物质，并保留了记忆和运动功能。此外，我们发现，除了能够阻断神经内神经元和细胞外A的毒性和形成外，铅TPS还增加了细胞胆固醇外排，恢复轴突运输，并增强海马突触位置 - 这些合成细胞作用可能是体内作用的潜在机制。这些铅TP化合物的发现来自医学化学家Hua博士，AD神经病理学专家Jin博士以及最近的PI博士，他在药品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Xie博士始于开发SmartCagetm系统，然后利用转化研究中的技术。 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 extreme) profiles of lead化合物。我们将重点介绍口服对AD模型APP/PS1小鼠的铅化合物的体内效率（神经性和神经病理学成果）。这些研究将使用可药物PK概况的标准，体内效率，尤其是认知方面的标准，提供基于证据的治疗候选者的选择，并提高病理性结果。 2。新型铅化合物的利用LRL22和LRL50作为备用化合物，并在需要的良好制造实践（GMP）生产所选治疗候选者的情况下进行准备。尽管我们已经确定了五种顶部备份TP化合物，但我们将使用先前发现的新型铅LRL22和LRL50，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作用的抑制作用。如果CP2和TP70不能满足治疗候选者的标准，则备份化合物将被重新合成并准备在体内进行测试。我们还将优化化学合成过程，以准备为II期研究确定的治疗候选者的GMP生产。在I阶段研究中的成功将为II期项目中的研究新药（IND）做准备。我们的最终目标是将新型TP化合物的临床前发现转化为假定AD疾病改良特性的临床治疗候选者。