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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.

本U01申请书(《阿尔茨海默病药物开发计划》，PAR-05-148) 建立在弗吉尼亚·李和约翰·特罗亚诺夫斯基(U01)最近里程碑式的观察基础上这为微管(MT)稳定剂的假设提供了令人信服的支持在治疗阿尔茨海默病(AD)和相关的神经退行性疾病方面前景看好。这一假说的核心是理解中枢神经系统中稳定MT的tau蛋白系统(CMS)被隔离成丝状包裹体，这是AD及其相关疾病的标志性病变 Tau病，从而损害tau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，该U01计划的中心推力是确定和评估潜在的MT稳定剂作为新的候选药物。极其重要的问题将解决的与化合物选择相关的问题包括全身毒性和在中枢神经系统中的可用性。为此，并鉴于在合成和生物评价方面取得的长足进展自我们最初的U01申请提交以来，来自不同类别天然产品的MT稳定剂 2006年2月，埃替罗酮被确定为先导结构。因此，我们建议合成根据我们的初步研究和发表的报告，选择了八到十(8-10)个埃普罗酮，是已知的或预计是中枢神经系统渗透剂，主要目的是鉴定化合物通过体外和体内筛选计划，将：(A)具有有效的大脑吸收，(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，以及(C)具有可忽略的全身毒性。初步的体外/体内试验已被设计用于评估疗效、PK、毒性和类药物性质。然后，成功的候选人将通过体内疗效和正常耐受性研究来表征老鼠。最有希望的候选人将接受使用两种不同的转基因动物进行的疗效研究模特们。最后，为最有希望的候选人开发有效的放大合成将允许进行更多的药代动力学和毒理学研究，以确定可行的候选者向研究性新药(IND)应用迈进。

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.