Alzhelmer's Disease Drug Development Program

阿尔茨海默病药物开发计划

• 批准号: 7676129
• 负责人: Amos B Smith
• 金额: $ 64.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/7676129
• 关键词: Address; Alzheimer' 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 Drugs; 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 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

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）：这项来自宾夕法尼亚大学的U01申请（“阿尔茨海默病药物开发计划”，PAR-05-148）建立在Virginia Lee和John Trojanowski （U01研究者）最近具有里程碑意义的观察基础上，这些观察为微管（MT）稳定剂在治疗阿尔茨海默病（AD）和相关神经退行性疾病方面具有巨大前景的假设提供了强有力的支持。这一假设的核心是理解中枢神经系统（CMS）的MT稳定tau蛋白被隔离在丝状包涵体中，这是AD和相关tau病的标志性病变，从而损害了tau在稳定和维持轴突运输和轴突存活所必需的MT网络中的正常功能。因此，这个U01项目的中心任务是识别和评估潜在的mt稳定剂作为新的候选药物。与化合物选择相关的至关重要的问题将包括中枢神经系统的系统毒性和可用性。为此，鉴于我们自2006年2月提交最初的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，我们已将埃波霉素确定为铅结构。因此，根据我们的初步研究和已发表的报告，我们建议合成八到十（8-10）种已知或预计可穿透中枢神经系统的艾替酮，其总体目标是通过体外和体内筛选程序识别化合物，这些化合物将：(A)具有有效的脑吸收，(B)增加中枢神经系统有丝分裂后神经元mt网络的稳定性，(C)具有可忽略的全身毒性。最初的体外/体内试验旨在评估其功效、PK、毒性和药物样特性。成功的候选药物将通过正常小鼠的体内疗效和耐受性研究来表征。最有希望的候选药物将采用两种不同的Tg动物模型进行疗效研究。最后，对最有希望的候选药物进行有效的规模化合成，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，推进研究新药（IND）申请。