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: 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
• 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' 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; 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

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病的新型三环吡喃酮药物的开发阿尔茨海默病(AD)困扰着全世界大约3500万人，并且是老年人痴呆的最常见原因。对于新的AD的医疗需求尚未得到满足。沉积在 AD 大脑中的淀粉样蛋白 -b (Ab) 已被用来引发一系列分子变化，导致 AD 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Ab及其下游事件的疗法已成为AD药物开发的主要工作，我们采取了合理的设计方法并合成了一类三环吡喃酮化合物（TPs）。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膜内施用化合物可显着减少可溶性和不溶性抗体种类。此外，我们发现除了能够阻断神经元内和细胞外 A 的毒性和形成之外。聚集体中，先导 TP 还可以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作用的潜在机制 这些先导 TP 化合物的发现来自药物化学家华博士、AD 神经病理学专家金博士和最近的 PI 谢博士之间的合作。 AfaSci 的 Xie 博士在制药领域拥有丰富的经验，为中枢神经系统治疗领域的药物开发做出了贡献，他从开发 SmartCageTM 系统开始，然后在转化研究中利用了该技术。项目在第一期 SBIR 的支持下，我们将通过实现以下具体目标，深入研究先导 TP 的药代动力学 (PK) 和体内药效学 (PD)： 1. 重点研究两种新型先导化合物 CP2 和 TP70治疗研究：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，我们将重点研究体内功效（神经行为和神经病理学）。通过口服给 AD 模型 APP/PS1 小鼠先导化合物的结果）这些研究将使用可药物 PK 曲线、体内功效（尤其是认知方面）和改善的标准来提供基于证据的治疗候选药物选择。 2. 如果需要，利用新型先导化合物 LRL22 和 LRL50 作为备用化合物，并为所选治疗候选药物的良好生产规范 (GMP) 生产做好准备 虽然我们已经确定了五种顶级备用 TP 化合物。先前发现的新先导化合物 LRL22 和 LRL50 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作用，作为备用化合物将被重新合成并准备进行测试。如目标 1 中所述，如果 CP2 和 TP70 均不符合候选治疗药物的标准，我们还将优化化学合成工艺，为已确定的候选治疗药物的 GMP 生产做好准备，以实现 I 期研究的成功。该研究将为 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的新型 TP 化合物的临床前发现转化为具有 AD 疾病缓解特性的临床治疗候选药物。