A Diarylheptanoid Scaffold to Treat Taopathies
治疗道病的二芳基庚烷支架
基本信息
- 批准号:8592264
- 负责人:
- 金额:$ 28.63万
- 依托单位:
- 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:2013-08-01 至 2014-07-31
- 项目状态:已结题
- 来源:
- 关键词:ADME StudyActive Biological TransportAlzheimer&aposs DiseaseAmyloidAnimal ModelAreaBase of the BrainBindingBiochemicalBiochemistryBiological AssayBiological AvailabilityBiological FactorsBrainBusinessesCellsCharacteristicsChemicalsClinicalClinical TrialsDevelopmentDiseaseDrug IndustryDrug KineticsExcretory functionFractionationFrontotemporal DementiaG Protein-Coupled Receptor GenesGenesGoalsGuidelinesHerbal MedicineHumanImpaired cognitionInheritedIntellectual PropertyIon ChannelLegal patentLibrariesLinkLiteratureLiver MicrosomesMeasuresMetabolismMethodsMusMutationMyricaNMR SpectroscopyNeurodegenerative DisordersOralOral AdministrationOutcome MeasurePathologyPatientsPenetrationPharmaceutical PreparationsPharmacodynamicsPhasePlasma ProteinsPreparationPrincipal InvestigatorProcessProductionProgressive Supranuclear PalsyPropertyProtein BindingQualifyingRattusReagentReportingResearchRouteSeriesSliceSmall Business Technology Transfer ResearchStereoisomerStructural ProteinStructure-Activity RelationshipSymptomsSynthesis ChemistrySystemTauopathiesTestingTherapeuticTransport ProcessUniversitiesValidationWorkabsorptionanalogbaseclinically relevantcommercializationcompliance behaviorcorticobasal degenerationdrug candidatedrug discoveryenantiomerexperienceimprovedin vivointerestmembermouse modelneuron lossnoveloverexpressionpre-clinicalprofessorprogramspublic health relevancepublic-private partnershipreceptorresearch clinical testingresearch studyscaffoldtau Proteinstau aggregationtau mutationtau-1toolwater solubility
项目摘要
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.
描述:我们通过系统筛选鉴定了杨梅提取物作为结构蛋白tau的有效减减剂,该蛋白在一组称为“tau病”的疾病中积累。最常见的tau病是阿尔茨海默病,人们对确定基于tau的治疗方法来治疗这种毁灭性疾病重新产生了兴趣;然而,tau基因突变是某些额颞叶痴呆(FTD)、进行性核上性麻痹(PSP)和皮质基底变性(CBD)病例的明确原因。很少有治疗策略针对tau蛋白,尽管它被认为是导致这些tau病中神经元损失的关键因素。事实上,在野生型或突变型tau过度表达的小鼠模型中,消耗tau已显示出改善认知障碍的希望。有机提取、生物活性驱动分馏法和核磁共振波谱法鉴定杨梅中环二芳基七烷杨梅醇是降低tau蛋白水平的主要活性成分之一。杨梅醇的一种以前未被鉴定的对映体[(S)-杨梅醇]是杨梅中产生的主要物种,并被发现主要负责降低tau活性。(S)-杨梅醇没有违反利平斯克指南,作为一种天然产品,可能会受到主动运输过程的影响,这可能对口服给药途径有用。(S)-杨梅醇是一种易于处理的候选药物,作为一种潜在的治疗药物和进一步发展结构活性关系的新支架。因此,随着急需抗tau药物来治疗AD及相关的tau病变,我们将:1)改进从杨梅中分离(+)-S-杨梅醇的方法;2)在初步SAR开发的指导下,开发一种高产立体选择性合成(S)-杨梅醇的途径,这也将适用于制备新的衍生物;3)确定(S)-杨梅醇和有限子集衍生物的功效并进行eADME(早期吸收、分布、代谢和排泄)研究。eADME的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在内的宽受体和离子通道分析,以及大鼠的初始药代动力学测试。我们将寻求指导我们的项目,以确定适合每日一次,口服给药治疗牛头病的药物,以增加患者的依从性和渗透。我们还将继续研究(S)-杨梅醇的作用机制,使用多管齐下的方法,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,作为在动物模型中进行临床前评估的探针,并提供体内概念验证,作为进入STTR计划的第二阶段的跳板,最终进行临床前开发和商业化。
项目成果
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Chad A. Dickey其他文献
Chad A. Dickey的其他文献
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{{ truncateString('Chad A. Dickey', 18)}}的其他基金
The hsp90 Cochaperone FKBP51 Regulates tau Structure and Function
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- 批准号:
9272217 - 财政年份:2016
- 资助金额:
$ 28.63万 - 项目类别:
Modeling stress-related psychopathology through FKBP5 manipulation
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- 批准号:
8923342 - 财政年份:2014
- 资助金额:
$ 28.63万 - 项目类别:
Modeling stress-related psychopathology through FKBP5 manipulation
通过 FKBP5 操作模拟压力相关的精神病理学
- 批准号:
8842846 - 财政年份:2014
- 资助金额:
$ 28.63万 - 项目类别:
Hsp70/DnaJ interface as a drug target for Alzheimer's disease and TBI
Hsp70/DnaJ 界面作为阿尔茨海默病和 TBI 的药物靶点
- 批准号:
8330372 - 财政年份:2012
- 资助金额:
$ 28.63万 - 项目类别:
Hsp70/DnaJ interface as a drug target for Alzheimer's disease and TBI
Hsp70/DnaJ 界面作为阿尔茨海默病和 TBI 的药物靶点
- 批准号:
8764624 - 财政年份:2012
- 资助金额:
$ 28.63万 - 项目类别:
Hsp70/DnaJ interface as a drug target for Alzheimer's disease and TBI
Hsp70/DnaJ 界面作为阿尔茨海默病和 TBI 的药物靶点
- 批准号:
8597937 - 财政年份:2012
- 资助金额:
$ 28.63万 - 项目类别:
The Hsp90 cochaperone FKBP51 regulates tau structure and function
Hsp90 辅助伴侣 FKBP51 调节 tau 结构和功能
- 批准号:
8240435 - 财政年份:2011
- 资助金额:
$ 28.63万 - 项目类别:
The Hsp90 cochaperone FKBP51 regulates tau structure and function
Hsp90 辅助伴侣 FKBP51 调节 tau 结构和功能
- 批准号:
8584376 - 财政年份:2011
- 资助金额:
$ 28.63万 - 项目类别:
The Hsp90 cochaperone FKBP51 regulates tau structure and function
Hsp90 辅助伴侣 FKBP51 调节 tau 结构和功能
- 批准号:
8086376 - 财政年份:2011
- 资助金额:
$ 28.63万 - 项目类别:
The Hsp90 cochaperone FKBP51 regulates tau structure and function
Hsp90 辅助伴侣 FKBP51 调节 tau 结构和功能
- 批准号:
8392290 - 财政年份:2011
- 资助金额:
$ 28.63万 - 项目类别: