Synthetic LXRbeta Ligands in the Treatment of Alzheimer's Disease

合成 LXRbeta 配体治疗阿尔茨海默病

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是一种使人衰弱的神经退行性疾病，与涉及记忆、学习和行为的大脑区域中的神经元死亡有关。由于 AD 的发病率迅速上升，而现有药物的效果甚微，对疾病进展的改善甚微（如果有的话），因此迫切需要新型抗 AD 药物。 AD 发展的一个核心事件是淀粉样前体蛋白 (APP) 加工的改变以及随后产生和聚集神经毒性形式的淀粉样 b 肽 (Ab)。 Ab 聚集体的积累似乎会引发或促进 AD 特征的神经元变性。因此，理所当然的是，治疗 AD 的理想分子靶标是能够调节抗体产生和/或积累的分子靶标。理想的 AD 靶标的另一个特征是易于“成药”的分子，即与药物样小分子相互作用的靶标，并且适合高通量筛选。核受体 LXR 满足这两个要求，因为它受到小分子配体的调节，并且已被证明可以减少培养细胞和体内抗体的产生。 Ab 的减少需要 LXR 介导的胆固醇流出泵 ABCA1 的激活。已鉴定出 LXR 的两种亚型：LXRa 和 LXRb。 b 亚型普遍表达，敲除研究表明它在大脑中很活跃。这种 b 亚型可能是降低抗体水平最有用的目标。相比之下，LXRa 亚型在代谢组织中高度表达，在代谢组织中激活 SREBP-1c 和脂肪酸合酶 (FAS) 的表达，从而导致甘油三酯水平急剧升高。这一主要副作用限制了非选择性 LXRa/b 激动剂的临床开发。然而，现有证据表明 LXRb 选择性激动剂应该没有这种副作用。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。使用这些先导化合物，我们提出了一系列化学合成来优化该先导化合物，并最终在体外和 AD 小鼠模型中测试 LXRb 选择性配体的功效。