Drug Discovery for Alzheimer's Disease

阿尔茨海默病的药物发现

• 批准号: 6645105
• 负责人: Aida Abraha
• 金额: $ 40.38万
• 依托单位: NEURONAUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6645105
• 关键词: Agnatha; Alzheimer's disease; brain disorder chemotherapy; disease /disorder model; drug discovery /isolation; drug screening /evaluation; electron microscopy; immunocytochemistry; neural degeneration; neurofibrillary tangles; neuropharmacologic agent; peptide library; pharmacokinetics; polymerization; protein isoforms; recombinant proteins; tau proteins

DESCRIPTION (provided by applicant): NNI seeks to ameliorate neurodegeneration seen in Alzheimer's disease and other dementias. Toward this end, NNI scientists have targeted neurofibrillary tangle (NFT) formation for drug discovery. These lesions appear in concert with the onset of memory loss in AD, and are in fact the best markers for AD neurodegeneration known in the scientific literature. Thus NNI has pursued agents that interfere with NFT formation. As part of Phase I effort, the feasibility of inhibiting tau filament formation and driving filament depolymerization in vitro using small, drug-like ligands was demonstrated. Moreover, the ability of one such molecule to halt progression of neurodegeneration in an animal model of disease was shown. The goal of Phase II effort is to extend these results by validating tau fibrillization as a drug target, and proving that in vitro screening technology can successfully identify compounds that are active in animal models of tau-induced neurodegeneration. There are three Aims. First, NNI will expand its screening effort to identify additional classes of molecules with anti tau polymerization activity. NNI has shown the feasibility of using its screening technology to identify such molecules. Second, NNI will characterize the mechanism of action of its compounds, establishing a structure activity relationship for members of the existing structural family. Finally, NNI will examine the activity of active compounds in vivo, demonstrating entry into the brain, and determining a structure activity relationship for in vivo activity. At the end of the project, NNI will be in position to establish neuritic lesions (e.g., NFTs) as an authentic target for intensive preclinical development.

描述（由申请人提供）：NNI 寻求改善阿尔茨海默病和其他痴呆症中出现的神经退行性疾病。为此，NNI 科学家将神经原纤维缠结 (NFT) 的形成作为药物发现的目标。这些病变与 AD 中记忆丧失的发生一致，实际上是科学文献中已知的 AD 神经变性的最佳标志。因此，NNI 一直在寻找干扰 NFT 形成的药物。作为第一阶段工作的一部分，证明了使用小型药物样配体在体外抑制 tau 丝形成和驱动丝解聚的可行性。此外，在动物疾病模型中，这种分子具有阻止神经变性进展的能力。 II 期工作的目标是通过验证 tau 纤维化作为药物靶点来扩展这些结果，并证明体外筛选技术可以成功识别在 tau 诱导的神经变性动物模型中具有活性的化合物。有三个目标。首先，NNI 将扩大筛选工作，以确定具有抗 tau 聚合活性的其他类别的分子。 NNI 已经展示了使用其筛选技术来识别此类分子的可行性。其次，NNI 将表征其化合物的作用机制，为现有结构家族的成员建立结构活性关系。最后，NNI 将检查活性化合物的体内活性，证明其进入大脑，并确定体内活性的结构活性关系。在项目结束时，NNI 将能够建立神经炎性病变（例如 NFT）作为强化临床前开发的真实目标。