Synthetic LXRbeta Ligands in the Treatment of Alzheimer's Disease

合成 LXRbeta 配体治疗阿尔茨海默病

• 批准号: 7282679
• 负责人: Barry M. Forman
• 金额: $ 17.44万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282679
• 关键词: ADD-1 protein; Adverse effects; Affinity; Agonist; Alzheimer' s Disease; Amyloid; Atherosclerosis; Behavior; Biological Assay; Brain; Brain region; Cell Culture System; Cells; Cessation of life; Characteristics; Cholesterol; Clinical; Complement; Cultured Cells; Deposition; Development; Disease Progression; Effectiveness; Elevation; Event; Fatty-acid synthase; Gene Targeting; Human; In Vitro; Incidence; Knock-out; Lead; Learning; Ligand Binding; Ligands; Mediating; Memory; Metabolic; Molecular Target; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear Receptors; Null Lymphocytes; Pan Genus; Pathology; Peptides; Pharmaceutical Preparations; Production; Proteins; Relative (related person); Reporter Genes; Series; Small Interfering RNA; Structure; Testing; Tg2576; Therapeutic Agents; Tissues; Triglycerides; Validation; amyloid precursor protein processing; base; chemical synthesis; design; efflux pump; high throughput screening; improved; in vivo; knock-down; mouse model; neurotoxic; novel; small molecule

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a debilitating neurodegenerative disorder associated with the death of neurons in brain regions involved in memory, learning and behavior. Novel anti-AD drugs are desperately needed as the incidence of AD is rapidly rising and existing drugs are minimally effective with little, if any, improvement in disease progression. A central event in the development of AD is the altered processing of amyloid precursor protein (APP) and the subsequent production and aggregation of neurotoxic forms of amyloid b peptide (Ab). Accumulation of Ab aggregates appears to initiate or promote the neuronal degeneration that is characteristic of AD. Therefore, it stands to reason that an ideal molecular target for the treatment of AD is one that can modulate the production and/or accumulation of Ab. A further characteristic of an ideal AD target would be a molecule that is readily "druggable", i.e. a target that interacts with small drug-like molecules and one that is amenable to high-throughput screening. The nuclear receptor LXR satisfies both requirements as it is modulated by small molecule ligands and has been shown to decrease the production of Ab in cultured cells and in vivo. Reduction in Ab requires an LXR-mediated activation of the cholesterol efflux pump ABCA1. Two subtypes of LXR have been identified: LXRa and LXRb. The b-subtype is ubiquitously expressed and knockout studies have shown that it is active in the brain. It is this b-subtype which is likely to be the most useful target for decreasing Ab levels. In contrast, the LXRa-subtype is highly expressed in metabolic tissues where it activates expression of SREBP-1c and fatty acid synthase (FAS), thus leading to dramatic elevations in triglyceride levels. This major side-effect has limited the clinical development of non-selective LXRa/b agonists. However, the available evidence suggests that LXRb-selective agonists should be free of this side-effect. In this application we provide the first examples of synthetic LXRb-selective agonists. Using these lead compounds we propose a series of chemical syntheses to optimize this lead and ultimately to test the efficacy of LXRb-selective ligands in vitro and in a mouse model of AD.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种与记忆，学习和行为有关的大脑区域中神经元死亡有关的神经退行性疾病。迫切需要新颖的抗AD药物，因为AD的发生率正在迅速上升，并且现有药物在疾病进展方面的改善中几乎没有（如果有的话）最少有效。 AD发展的中心事件是淀粉样蛋白（APP）的加工改变以及随后的淀粉样蛋白B肽（AB）的神经毒性形式的产生和聚集。 AB聚集体的积累似乎启动或促进了AD特征的神经元变性。因此，有理由认为AD治疗的理想分子靶标是可以调节AB的产生和/或积累的理想分子靶标。理想的AD靶标的进一步特征是一个很容易“可吸毒”的分子，即与小型药物样分子相互作用的靶标，并且可以适合高通量筛选。核受体LXR满足了这两种要求，因为它是由小分子配体调节的，并且已显示可降低培养细胞和体内的AB产生。降低AB需要LXR介导的胆固醇外排泵ABCA1的激活。 已经确定了两个LXR的亚型：LXRA和LXRB。 B-辅助型无处不在，敲除研究表明它在大脑中具有活性。正是这种B辅助类型可能是降低AB水平的最有用的目标。相比之下，LXRA-SUBTYPE在代谢组织中高度表达，在代谢组织中，它激活了SREBP-1C和脂肪酸合酶（FAS）的表达，从而导致甘油三酸酯水平的显着升高。这种主要的副作用限制了非选择性LXRA/B激动剂的临床发展。但是，可用的证据表明，LXRB选择性激动剂应没有这种副作用。在此应用中，我们提供了合成LXRB选择性激动剂的第一个例子。使用这些铅化合物，我们提出了一系列化学合成，以优化该铅，并最终在体外和AD小鼠模型中测试LXRB选择性配体的功效。