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：
8118501
负责人：
Amos B Smith
金额：
$ 60.96万
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/8118501
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

DESCRIPTION (provided by applicant): 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-penetrate, 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.

描述（由申请人提供）：宾夕法尼亚大学的这份 U01 申请（“阿尔茨海默病药物开发计划”，PAR-05-148）以 Virginia Lee 和 John Trojanowski（U01 研究人员）最近的里程碑式观察为基础，这些观察提供了令人信服的支持假设微管 (MT) 稳定剂对于治疗阿尔茨海默病 (AD) 和相关的神经退行性疾病具有广阔的前景。这一假说的核心是这样的认识：中枢神经系统 (CMS) 的 MT 稳定 tau 蛋白被隔离在丝状包涵体中，而丝状包涵体是 AD 和相关 tau 病的标志性病变，从而损害了 tau 稳定和维持 MT 的正常功能对于轴突运输和轴突生存至关重要的网络。因此，该 U01 项目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。将要解决的与化合物选择相关的至关重要的问题包括系统毒性和中枢神经系统的可用性。为此，鉴于自 2006 年 2 月提交原始 U01 申请以来，在不同类别天然产物的 MT 稳定剂的合成和生物学评价方面取得了相当大的进展，埃坡霉素已被确定为先导结构。因此，我们建议合成八到十（8-10）种选定的埃博霉素，根据我们的初步研究以及已发表的报告，这些埃博霉素已知或预计具有中枢神经系统渗透性，总体目标是通过体外和体外鉴定化合物。体内筛选程序将：（A）具有有效的脑摄取，（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，以及（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，将通过正常小鼠的体内功效和耐受性研究来表征成功的候选药物。最有希望的候选者将接受使用两种不同 Tg 动物模型的功效研究。最后，为最有希望的候选药物开发有效的放大合成将允许执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以推进研究性新药（IND）申请。