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.

该大学的U01应用程序（“阿尔茨海默氏病药物开发计划”，PAR-05-148）宾夕法尼亚州的建设是建立在弗吉尼亚·李和约翰·特洛伊诺夫斯基的最新地标观测的基础上（U01 研究人员）对微管（MT）稳定剂的假设提供了令人信服的支持对治疗阿尔茨海默氏病（AD）和相关神经退行性疾病的治疗有很大的希望。该假设的核心是理解中枢神经的MT稳定tau蛋白系统（CMS）被隔离为丝状包含，是AD和相关的签名病变 TAUOPATH，从而损害Tau在稳定和维持MT网络中的正常功能对于轴突运输和轴突存活所必需的。因此，该U01程序的中心推力是识别并评估潜在的MT稳定剂作为新型药物候选物。至关重要的问题与将要解决的化合物选择有关，包括中枢神经系统中的系统性毒性和可用性。为此，鉴于在综合和生物学评估中取得的重大进展自我们原始U01申请提交以来，来自不同类别天然产品的MT稳定代理在2006年2月，已确定雌激素为铅结构。因此，我们建议合成八到十（8-10）选择了基于我们的初步研究以及已发表的报告，已知或期望为CNS-PENETRANT，其总体目的是识别化合物通过体外和体内筛查程序将：（a）具有有效的大脑吸收，（b）增加 MT网络在中枢神经系统的有丝分裂神经元中的稳定性，（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，毒性和类似药物样特性。然后，成功的候选人将通过正常的体内功效和耐受性研究来表征老鼠。最有希望的候选人将接受两种不同的TG动物的功效研究型号。最后，开发有效的最有前途候选人的有效扩大合成将允许执行其他药代动力学和毒理学研究，以确定可行的候选者迈向研究新药（IND）应用。

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.

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

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 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

In situ blood-brain barrier permeability of a C-10 paclitaxel carbamate.

DOI：
10.1016/j.bmcl.2008.10.024
发表时间：
2008-12-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Ballatore, Carlo;Zhang, Bin;Trojanowski, John Q.;Lee, Virginia M. -Y.;Smith, Amos B., III
通讯作者：
Smith, Amos B., III