Brain penetrant Hsp90 inhibitors for Alzheimer's disease
Brain penetrant Hsp90 inhibitors for Alzheimer's disease
批准号:
8780832
负责人:
MARCIE A GLICKSMAN
金额:
$95.86万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-01 至 2016-06-30
关键词:
AddressAffectAftercareAlzheimer&aposs DiseaseAmygdaloid structureAmyloid beta-ProteinAwardBackBehavioralBiochemicalBiological AssayBiological MarkersBrainCerebrospinal FluidClinicalClinical TreatmentCyclin-Dependent KinasesDataDepositionDeteriorationDevelopmentDiseaseDisease ProgressionDoseDrug FormulationsDrug KineticsFundingGenerationsHSP 90 inhibitionHealthHeat Stress DisordersHeat-Shock Proteins 90Hippocampus (Brain)HumanIn VitroIndividualInvestigational New Drug ApplicationLeadLearningMeasurementMemoryMolecular ChaperonesMonitorMusNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsOutcomePathway interactionsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhasePropertyProteinsPublishingRegimenReportingResearchResearch SupportRoleRunningSafetySmall Business Technology Transfer ResearchSodiumSolubilityStructure-Activity RelationshipTauopathiesTherapeuticTimeTimeLineTissuesToxicologyTransgenic MiceValidationVariantWorkabnormally phosphorylated tauagedanticancer researchbehavior measurementbrain tissuecancer therapydrinking waterdrug candidateimprovedin vivoinhibitor/antagonistmanufacturing scale-upmild cognitive impairmentmorris water mazemouse modelneuropathologynovelnovel strategiesphase 2 studyprotein degradationselenatetau Proteinstau aggregationtau mutationtau phosphorylationtau-1therapy developmenttransgenic model of alzheimer diseasetreatment effecttumor growth
中文摘要
描述(由申请人提供):阿尔茨海默病(AD)中的神经变性可能是由于Aβ在脑组织中沉积为斑块所致。然而,较少的努力已经阐明了含tau蛋白的神经元缠结(NFT)在AD中的作用。越来越多的证据表明,含tau的NFT是AD和其他神经退行性疾病的起始和进展中的重要组分。在这个提议中,tau通路是通过抑制分子伴侣热休克蛋白90(Hsp 90)作为一个有前途的新方法来影响AD的疾病进展的目标。该提案建立在STTR I期资助下提出和实现的具体目标基础上- a)进行结构-活性关系研究以获得脑渗透性Hsp 90抑制剂和B)评估生物化学和细胞Hsp 90抑制。这些努力产生了具有可接受的药物样性质的新型专有Hsp 90抑制剂,包括良好的脑浓度。自I期资助结束以来,尤马治疗公司已经在小鼠中获得了早期先导化合物YT-17的药代动力学数据,进一步支持了其药物样特性。II期拟定研究的重点是a)在tau蛋白病体内转基因小鼠模型中评价我们的先导化合物对脑脊液中总tau蛋白和磷酸化tau蛋白水平、tau神经病理学和行为结果的影响; B)先导候选药物活性药物成分(API)的生产规模扩大,并启动体内毒理学研究;以及c)API的配制工作。
英文摘要
DESCRIPTION (provided by applicant): Neurodegeneration in Alzheimer's disease (AD) may result from deposition of Aβ as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone heat shock protein 90 (Hsp90) as a promising new approach to affect the disease progression of AD. This proposal builds on the specific aims set forth and achieved under the STTR Phase I funding - a) to conduct structure-activity relationship studies to obtain brain permeable Hsp90 inhibitors and b) to evaluate biochemical and cellular Hsp90 inhibition. These efforts yielded novel, proprietary Hsp90 inhibitors with acceptable drug-like properties including good brain concentration. Since the conclusion of Phase I funding, Yuma Therapeutics has generated pharmacokinetic data in mice for an early lead compound, YT-17, further supporting its drug-like properties. The proposed studies for Phase II focus on a) evaluating our lead compound in an in vivo transgenic mouse model of tauopathy on the levels of total tau and phosphorylated-tau in cerebrospinal fluid, tau neuropathology, and behavioral outcomes; b) manufacturing scale-up of active pharmaceutical ingredient (API) of a lead candidate and initiate in vivo toxicology studies; and c) formulation work on the API.
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依托单位:
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依托单位:
海外基金