Alzhelmer's Disease Drug Development Program
阿尔茨海默病药物开发计划
基本信息
- 批准号:8287605
- 负责人:
- 金额:$ 59.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-01 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAmyloid FibrilsAmyloidosisAnimal ModelAxonAxonal TransportBiologicalBiological AssayBiological FactorsBlood - brain barrier anatomyBrainCentral Nervous System DiseasesCollaborationsDataDepositionDevelopmentDiseaseDoseDose-LimitingDrug KineticsDrug toxicityEpothilonesEvaluationFrontotemporal DementiaGoalsHumanIn VitroInvestigational New Drug ApplicationLeadLesionLightMaximum Tolerated DoseMetabolicMicrotubule stabilizing agentMicrotubulesMusNOELNerve DegenerationNeuraxisNeuritesNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPaclitaxelPathologyPenetrationPennsylvaniaPharmaceutical PreparationsPlasmaProcessPropertyPublishingReportingResearch PersonnelSafetySamplingScreening procedureSenile PlaquesStructureTauopathiesTestingTherapeuticToxic effectTransgenic AnimalsTransgenic MiceTransgenic OrganismsUniversitiesVirginiaage relatedbasecytotoxicitydesigndrug candidatedrug developmentdrug discoveryextracellulargenotoxicityin vitro Assayin vivointerestmouse modelneurodegenerative phenotypenovelpre-clinicalprogramsscale uptau Proteinstau functionuptake
项目摘要
This U01 application ("Alzheimer's Disease Drug Development Program", PAR-05-148) from the University
of Pennsylvania builds on the recent landmark observations of Virginia Lee and John Trojanowski (U01
investigators) that provide compelling support for the hypothesis that microtubule (MT)-stabilizing agents
hold great promise for the treatment of Alzheimer's disease (AD) and related neurodegenerative diseases.
Central to this hypothesis is the understanding that the MT-stabilizing tau proteins of the central nervous
system (CMS) are sequestered into filamentous inclusions that are the signature lesions of AD and related
tauopathies, thereby compromising the normal function of tau in stabilizing and maintaining MT networks
essential for axonal transport and axon survival. The central thrust of this U01 program is therefore to
identify and evaluate potential MT-stabilizing agents as novel drug candidates. Critically important issues
related to compound selection that will be addressed include systemic toxicity and availability in the CNS.
To this end, and in light of the considerable progress made both in the synthesis and biological evaluation of
MT-stabilizing agents from different classes of natural products since our original U01 application submitted
in February of 2006, epothilones have been identified as lead structures. We therefore propose to synthesize
eight to ten (8-10) selected epothilones, that based on our preliminary studies as well as published reports,
are either known or expected to be CNS-penetrant, with the overarching aim of identifying compounds
through in vitro and in vivo screening programs that will: (A) possess effective brain uptake, (B) increase the
stability of MT-networks in postmitotic neurons of the CNS, and (C) possess negligible systemic toxicity.
Initial in vitro/in vivo assays have been designed to evaluate efficacy, PK, toxicity and drug-like properties.
Successful candidates will then be characterized through in vivo efficacy and tolerability studies in normal
mice. The most promising candidates will be subjected to efficacy studies employing two distinct Tg animal
models. Finally, development of an effective scale-up synthesis for the most promising candidate will permit
execution of additional pharmacokinetic and toxicological studies, in order to identify a viable candidate to
advance towards an Investigational New Drug (IND) application.
来自大学的 U01 申请(“阿尔茨海默病药物开发计划”,PAR-05-148)
宾夕法尼亚州的研究建立在弗吉尼亚·李和约翰·特洛伊诺夫斯基最近具有里程碑意义的观察之上(U01
研究人员)为微管(MT)稳定剂的假设提供了令人信服的支持
对于治疗阿尔茨海默病(AD)和相关的神经退行性疾病具有巨大的前景。
这一假说的核心是理解中枢神经系统的 MT 稳定 tau 蛋白
系统(CMS)被隔离在丝状包涵体中,这是 AD 和相关疾病的标志性病变
tau 蛋白病,从而损害 tau 蛋白稳定和维持 MT 网络的正常功能
对于轴突运输和轴突生存至关重要。因此,该 U01 计划的中心目标是
识别和评估潜在的 MT 稳定剂作为新候选药物。至关重要的问题
与将要解决的化合物选择相关的问题包括全身毒性和中枢神经系统的可用性。
为此,鉴于在合成和生物学评价方面取得的巨大进展
自我们最初提交 U01 申请以来,来自不同类别天然产品的 MT 稳定剂
2006年2月,埃坡霉素被确定为先导结构。因此我们建议综合
八到十 (8-10) 个选定的埃坡霉素,基于我们的初步研究以及已发表的报告,
已知或预期具有中枢神经系统渗透性,总体目标是识别化合物
通过体外和体内筛选计划,将:(A)拥有有效的大脑摄取,(B)增加
中枢神经系统有丝分裂后神经元中 MT 网络的稳定性,(C) 具有可忽略的全身毒性。
最初的体外/体内测定旨在评估功效、PK、毒性和药物样特性。
然后,将通过正常情况下的体内功效和耐受性研究来表征成功的候选者。
老鼠。最有前途的候选者将接受使用两种不同 Tg 动物的功效研究
模型。最后,为最有希望的候选者开发有效的放大合成将允许
进行额外的药代动力学和毒理学研究,以确定可行的候选药物
推进研究性新药 (IND) 申请。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Solid phase synthesis of 2-aminobenzothiazoles.
- DOI:10.1016/j.bmcl.2009.11.055
- 发表时间:2010-01-15
- 期刊:
- 影响因子:2.7
- 作者:Piscitelli, Francesco;Ballatore, Carlo;Smith, Amos B., III
- 通讯作者:Smith, Amos B., III
Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D.
海马中Aβ介导的脊柱变化是微管依赖性的,可以通过微管稳定剂EpothiloneD的亚洋摩尔浓度逆转。
- DOI:10.1016/j.neuropharm.2016.01.002
- 发表时间:2016-06
- 期刊:
- 影响因子:4.7
- 作者:Penazzi L;Tackenberg C;Ghori A;Golovyashkina N;Niewidok B;Selle K;Ballatore C;Smith AB 3rd;Bakota L;Brandt R
- 通讯作者:Brandt R
The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice.
- DOI:10.1523/jneurosci.4922-11.2012
- 发表时间:2012-03-14
- 期刊:
- 影响因子:0
- 作者:Zhang B;Carroll J;Trojanowski JQ;Yao Y;Iba M;Potuzak JS;Hogan AM;Xie SX;Ballatore C;Smith AB 3rd;Lee VM;Brunden KR
- 通讯作者:Brunden KR
Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.
- DOI:10.1016/j.bmc.2013.12.046
- 发表时间:2014-09-15
- 期刊:
- 影响因子:3.5
- 作者:Brunden KR;Trojanowski JQ;Smith AB 3rd;Lee VM;Ballatore C
- 通讯作者:Ballatore C
Microtubule stabilizing agents as potential treatment for Alzheimer's disease and related neurodegenerative tauopathies.
- DOI:10.1021/jm301079z
- 发表时间:2012-11-08
- 期刊:
- 影响因子:7.3
- 作者:Ballatore, Carlo;Brunden, Kurt R.;Huryn, Donna M.;Trojanowski, John Q.;Lee, Virginia M. -Y.;Smith, Amos B., III
- 通讯作者:Smith, Amos B., III
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Amos B Smith其他文献
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Dictyostatin and related prodrugs as candidates for tauopathy treatment
Dictyostatin 和相关前药作为 tau 蛋白病治疗的候选药物
- 批准号:
8821175 - 财政年份:2014
- 资助金额:
$ 59.19万 - 项目类别:
Pilot-Scale Libraries for High-throughput Screening
用于高通量筛选的中试规模文库
- 批准号:
7291136 - 财政年份:2007
- 资助金额:
$ 59.19万 - 项目类别:
Pilot-Scale Libraries for High-throughput Screening
用于高通量筛选的中试规模文库
- 批准号:
7684229 - 财政年份:2007
- 资助金额:
$ 59.19万 - 项目类别:
Pilot-Scale Libraries for High-throughput Screening
用于高通量筛选的中试规模文库
- 批准号:
7497036 - 财政年份:2007
- 资助金额:
$ 59.19万 - 项目类别: