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（申请人提供）：U 01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最近具有里程碑意义的观察基础上（U 01研究人员），为微管（MT）稳定剂对治疗阿尔茨海默病（AD）有很大希望的假设提供了令人信服的支持。和相关的神经退行性疾病。该假设的核心是理解中枢神经系统（CMS）的MT稳定化tau蛋白被隔离到丝状包涵体中，所述丝状包涵体是AD和相关tau蛋白病的特征性病变，从而损害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，该U 01计划的中心目标是识别和评估潜在的MT稳定剂作为新型候选药物。将讨论的与化合物选择相关的至关重要的问题包括全身毒性和CNS中的可用性。为此，鉴于自我们于2006年2月提交的原始U 01申请以来，在来自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的相当大的进展，埃博霉素已被确定为先导结构。因此，我们建议合成八至十（8-10）种选定的埃坡霉素，其基于我们的初步研究以及已发表的报告，已知或预期是CNS渗透的，总体目标是通过体外和体内筛选程序鉴定化合物，所述筛选程序将：（A）具有有效的脑摄取，（B）增加CNS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/体内试验旨在评估功效、PK、毒性和药物样特性。然后将通过在正常小鼠中的体内功效和耐受性研究来表征成功的候选物。最有希望的候选物将采用两种不同的Tg动物模型进行功效研究。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。