Alzhelmer's Disease Drug Development Program

描述(由申请人提供)：这份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)建立在弗吉尼亚·李和约翰·特罗亚诺夫斯基(U01研究人员)最近的里程碑式观察的基础上，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的巨大前景提供了令人信服的支持。这一假说的核心是理解中枢神经系统(CMS)中稳定MT的tau蛋白被隔离在丝状包涵体中，这是AD和相关tauopy疾病的标志性病变，从而损害了tau在稳定和维持对轴突运输和轴突生存至关重要的MT网络中的正常功能。因此，U01计划的核心是确定和评估潜在的MT稳定剂作为新的候选药物。将解决的与化合物选择有关的至关重要的问题包括全身毒性和在中枢神经系统中的可用性。为此，鉴于自2006年2月我们首次提交U01申请以来，从不同类别的天然产品中合成和生物评价MT稳定剂方面取得了相当大的进展，Epothilone已被确定为先导结构。因此，我们建议合成八到十个(8-10)个选定的埃普罗酮类化合物，根据我们的初步研究和已发表的报告，这些化合物是已知或有望穿透中枢神经系统的，主要目的是通过体外和体内筛选程序鉴定化合物，这些化合物将：(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。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，将通过在正常小鼠身上进行体内疗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的TG动物模型进行的疗效研究。最后，为最有希望的候选药物开发有效的放大合成将允许进行更多的药代动力学和毒理学研究，以便确定一个可行的候选药物，以推进研究性新药(IND)的应用。

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.