A Diarylheptanoid Scaffold to Treat Taopathies

描述：我们通过系统筛选确定杨梅(杨梅)提取物是一种有效的结构蛋白tau的减少剂，tau在一组名为tauopathies的疾病中积累。最常见的互动症是阿尔茨海默病，人们对基于tau的治疗方法重新产生了兴趣，以治疗这种毁灭性的疾病；然而，tau基因的突变是一些额颞痴呆(FTD)、进行性核上性麻痹(PSP)和皮质基底性变性(CBD)的明确原因。很少有治疗策略针对tau蛋白，尽管它被视为在这些tau病中导致神经元丢失的关键因素。事实上，耗尽tau在改善野生型或突变型tau过度表达的小鼠模型中观察到的认知障碍方面显示出了希望。有机提取、生物活性驱动的分离和核磁共振光谱鉴定了环状二芳庚烷类杨梅醇是杨梅中参与降低tau水平的主要活性成分之一。杨梅醇的一种未知的对映体[(S)-杨梅醇]是杨梅中产生的主要物种，并被发现是降低tau活性的主要原因。(S)-肉豆蔻醇没有违反利平斯克指南，作为一种天然产物，可能会经历积极的转运过程，这可能对口服给药途径有用。(S)-杨梅醇本身是一种易于处理的候选药物，既是一种潜在的治疗药物，也是进一步开发结构活性关系的新支架。因此，随着治疗阿尔茨海默病和相关疾病的紧急抗tau药物的需要，我们将：1)改进从杨梅中分离()-S-杨梅醇的方法，2)开发一条高产量和立体选择性的合成(S)-杨梅醇的路线，该路线也将适合于基于我们初步的SAR开发指导下的新型衍生物的制备，以及3)确定(S)-杨梅醇的疗效并进行eADME(早期吸收、分布、代谢和排泄)研究和(S)-杨梅醇及其有限亚类衍生物的研究。EADME研究将包括小鼠和人肝微粒体的代谢、人血浆蛋白结合、水溶性测试、包括HERG在内的广泛受体和离子通道分析，以及大鼠的初步药代动力学测试。我们将寻求指导我们的计划，以确定适合每天一次的口服给药治疗紧张症，以增加患者的依从性和渗透率。我们还将继续研究(S)-杨梅醇的作用机制，采用多管齐下的方法，利用我们独特准备的工具和试剂来研究tau生物化学。最终，这些研究可以提供一系列新的天然产物衍生的降tau药物作为探针，用于以tauopathy为特征的动物模型的临床前评估，并提供体内概念验证，作为进入STTR计划第二阶段的跳板，最终进行临床前开发和商业化。

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.