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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：
Amos B Smith
金额：
$ 59.19万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
https://reporter.nih.gov/project-details/8287605
关键词：
Address Alzheimer&apos s Disease Amyloid Fibrils Amyloidosis Animal Model Axon Axonal Transport Biological Biological Assay Biological Factors Blood - brain barrier anatomy Brain Central Nervous System Diseases Collaborations Data Deposition Development Disease Dose Dose-Limiting Drug Kinetics Drug toxicity Epothilones Evaluation Frontotemporal Dementia Goals Human In Vitro Investigational New Drug Application Lead Lesion Light Maximum Tolerated Dose Metabolic Microtubule stabilizing agent Microtubules Mus NOEL Nerve Degeneration Neuraxis Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neurons Paclitaxel Pathology Penetration Pennsylvania Pharmaceutical Preparations Plasma Process Property Publishing Reporting Research Personnel Safety Sampling Screening procedure Senile Plaques Structure Tauopathies Testing Therapeutic Toxic effect Transgenic Animals Transgenic Mice Transgenic Organisms Universities Virginia age related base cytotoxicity design drug candidate drug development drug discovery extracellular genotoxicity in vitro Assay in vivo interest mouse model neurodegenerative phenotype novel pre-clinical programs scale up tau Proteins tau function uptake

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.

这U 01申请（“阿尔茨海默病药物开发计划”，PAR-05-148）从大学宾夕法尼亚州的研究建立在弗吉尼亚·李（Virginia Lee）和约翰·特罗贾诺夫斯基（John Trojanowski）（U 01）最近具有里程碑意义的观察基础上研究人员），提供了令人信服的支持的假设，微管（MT）稳定剂对阿尔茨海默病（AD）和相关神经退行性疾病的治疗具有巨大的希望。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）被隔离成丝状夹杂物，这是AD和相关疾病的标志性病变 tau蛋白病，从而损害tau蛋白在稳定和维持MT网络中的正常功能对轴突运输和轴突存活至关重要。因此，U 01计划的核心是鉴定和评价作为新型候选药物的潜在MT稳定剂。极为重要的问题与化合物选择相关的将被解决的问题包括全身毒性和CNS中的可用性。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U 01申请以来，来自不同类别天然产品的MT稳定剂在2006年2月，埃坡霉素已被确定为先导结构。因此，我们建议综合八至十（8-10）种选择的埃博霉素，基于我们的初步研究以及公开的报道，已知或预期是CNS渗透剂，其首要目的是识别化合物通过体外和体内筛选程序，将：（A）具有有效的脑摄取，（B）增加 CNS的有丝分裂后神经元中MT网络的稳定性，和（C）具有可忽略的全身毒性。最初的体外/体内试验设计用于评价疗效、PK、毒性和药物样性质。成功的候选者将通过在正常人中的体内功效和耐受性研究来表征。小鼠最有希望的候选物将采用两只不同的Tg动物进行有效性研究模型最后，发展一个有效的放大合成的最有前途的候选人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，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：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
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：
Neuropharmacology
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：
The Journal of neuroscience : the official journal of the Society for Neuroscience
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：
Bioorganic & medicinal chemistry
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

The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies.

微管稳定药物的表征是阿尔茨海默氏病和相关tauopathies的治疗剂。

DOI：
10.1016/j.phrs.2010.12.002
发表时间：
2011-04
期刊：
PHARMACOLOGICAL RESEARCH
影响因子：
9.3
作者：
Brunden, Kurt R.;Yao, Yuemang;Potuzak, Justin S.;Ferrer, Nuria Ibarz;Ballatore, Carlo;James, Michael J.;Hogan, Anne-Marie L.;Trojanowski, John Q.;Smith, Amos B., III;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.