A Diarylheptanoid Scaffold to Treat Taopathies

治疗道病的二芳基庚烷支架

• 批准号: 8592264
• 负责人: Chad A. Dickey
• 金额: $ 28.63万
• 依托单位: ALS BIOPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592264
• 关键词: ADME Study; Active Biological Transport; Alzheimer' s Disease; Amyloid; Animal Model; Area; Base of the Brain; Binding; Biochemical; Biochemistry; Biological Assay; Biological Availability; Biological Factors; Brain; Businesses; Cells; Characteristics; Chemicals; Clinical; Clinical Trials; Development; Disease; Drug Industry; Drug Kinetics; Excretory function; Fractionation; Frontotemporal Dementia; G Protein-Coupled Receptor Genes; Genes; Goals; Guidelines; Herbal Medicine; Human; Impaired cognition; Inherited; Intellectual Property; Ion Channel; Legal patent; Libraries; Link; Literature; Liver Microsomes; Measures; Metabolism; Methods; Mus; Mutation; Myrica; NMR Spectroscopy; Neurodegenerative Disorders; Oral; Oral Administration; Outcome Measure; Pathology; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma Proteins; Preparation; Principal Investigator; Process; Production; Progressive Supranuclear Palsy; Property; Protein Binding; Qualifying; Rattus; Reagent; Reporting; Research; Route; Series; Slice; Small Business Technology Transfer Research; Stereoisomer; Structural Protein; Structure-Activity Relationship; Symptoms; Synthesis Chemistry; System; Tauopathies; Testing; Therapeutic; Transport Process; Universities; Validation; Work; absorption; analog; base; clinically relevant; commercialization; compliance behavior; corticobasal degeneration; drug candidate; drug discovery; enantiomer; experience; improved; in vivo; interest; member; mouse model; neuron loss; novel; overexpression; pre-clinical; professor; programs; public health relevance; public-private partnership; receptor; research clinical testing; research study; scaffold; tau Proteins; tau aggregation; tau mutation; tau-1; tool; water solubility

DESCRIPTION: We identified the Myrica cerifera (Southern Bayberry) extract using a systematic screen as a potent reducer of the structural protein tau, which accumulates in a group of diseases called the "tauopathies". The most prevalent tauopathy is Alzheimer's disease, for which there is renewed interest in the identification of tau- based therapeutic approaches to treat this devastating disease; however mutations in the tau gene are the unequivocal cause of some cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Few therapeutic strategies have targeted the tau protein, despite it being seen as the key factor contributing to neuronal loss in these tauopathies. In fact, depleting tau has shown promise in ameliorating the cognitive impairment observed in mouse models in which either wild-type or mutant tau is overexpressed. Organic extraction, bioactivity-driven fractionation and nuclear magnetic resonance spectroscopy identified the cyclic diarylheptanoid myricanol as one of the main active components from Bayberry involved in lowering tau levels. A previously-uncharacterized enantiomer of myricanol [(S)-myricanol] was the predominant species produced in Myrica cerifera, and found to be primarily responsible for the tau lowering activity. (S)-Myricanol has no violations of the Lipinsk guidelines and, as a natural product, may be subject to active transport processes which may be useful for the oral route of administration. (S)-Myricanol represents a tractable drug candidate for both on its own as a potential therapeutic and as a novel scaffold for further structure activity relationship development. Thus, with the need for emergent anti-tau drugs to treat AD and related tauopathies we will: 1) improve the isolation of (+)-S-myricanol from Myrica cerifera, 2) develop a high-yielding and stereoselective route for the production of synthetic (S)-myricanol which will also be amenable to the preparation of novel derivatives based upon guidance from our preliminary SAR development, and 3) determine the efficacy and conduct eADME (early absorption, distribution, metabolism, and excretion) studies on (S)-myricanol and a limited subset of derivatives. The eADME studies will include metabolism in mouse and human liver microsomes, human plasma protein binding, water solubility testing, broad receptor and ion channel profiling including hERG, and initial pharmacokinetic testing in rats. We would seek to direct our program to identify agents that would be suitable for once-daily, oral administration for the treatment of tauopathies, to increase patient compliance and penetration. We will also continue studies to characterize the mechanism of action of (S)-myricanol using a multipronged approach, taking advantage of tool and reagents that we have uniquely prepared to investigate tau biochemistry. Ultimately these studies could provide a novel series of natural-product derived tau-lowering agents as probes for pre-clinical evaluation in animal models characteristic of the tauopathies, and provide in vivo proof of concept validation to serve as a springboard into Phase II of the STTR program for eventual preclinical development and commercialization.

产品说明：我们使用系统筛选鉴定了杨梅（南方杨梅）提取物作为结构蛋白tau的有效还原剂，所述结构蛋白tau在一组称为“tau蛋白病”的疾病中积累。最普遍的tau蛋白病是阿尔茨海默病，对于阿尔茨海默病，重新关注鉴定基于tau的治疗方法以治疗这种破坏性疾病;然而，tau基因中的突变是额颞叶痴呆（FTD）、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）的一些病例的明确原因。很少有治疗策略靶向tau蛋白，尽管它被视为导致这些tau蛋白病中神经元丢失的关键因素。事实上，消除tau蛋白已经显示出改善小鼠模型中观察到的认知障碍的希望，其中野生型或突变型tau蛋白过表达。有机提取，生物活性驱动的分馏和核磁共振光谱鉴定的环状二芳基庚烷类杨梅醇的主要活性成分之一，从杨梅参与降低tau水平。先前未表征的杨梅醇对映体[（S）-杨梅醇]是在杨梅中产生的主要种类，并且发现其主要负责降低tau活性。（S）-杨梅醇没有违反Lipinsk指南，作为一种天然产品，可能会经历主动转运过程，这可能对口服给药途径有用。（S）-杨梅醇代表了一种易于处理的候选药物，其本身既作为潜在的治疗药物，又作为进一步开发结构活性关系的新型支架。因此，由于需要紧急的抗tau药物来治疗AD和相关的tau蛋白病，我们将：1）改进从杨梅中分离（+）-S-杨梅醇，2）开发用于生产合成（S）-杨梅醇的高产和立体选择性路线，其也将适合于基于我们初步SAR开发的指导制备新衍生物，和3）确定（S）-杨梅醇和有限的衍生物子集的功效并进行eADME（早期吸收、分布、代谢和排泄）研究。eADME研究将包括小鼠和人肝微粒体中的代谢、人血浆蛋白结合、水溶性试验、广泛受体和离子通道分析（包括hERG）以及大鼠中的初始药代动力学试验。我们将寻求指导我们的计划，以确定适合每日一次口服给药治疗tau蛋白病的药物，以增加患者的依从性和渗透性。我们还将利用我们为研究tau生物化学而专门准备的工具和试剂，采用多管齐下的方法继续研究（S）-杨梅醇的作用机制。最终，这些研究可以提供一系列新的天然产物衍生的tau蛋白降低剂作为探针，用于在tau蛋白病特征性动物模型中进行临床前评价，并提供体内概念验证，以作为进入STTR计划II期的跳板，用于最终的临床前开发和商业化。