Modulation of the Innate Immune Response by Fisetin Derivatives for the Treatment of AD

漆黄素衍生物调节先天免疫反应治疗 AD

• 批准号: 9138287
• 负责人: Pamela Anne Maher
• 金额: $ 77.14万
• 依托单位: VIROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138287
• 关键词: Accounting; Acute; Address; Age; Alzheimer' s Disease; Ames Assay; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Biochemical; Biological; Biological Assay; Biological Availability; Body part; Brain; Cardiotoxicity; Cells; Chemistry; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Cognition; Complement; Data; Deterioration; Development; Diabetes Mellitus; Disease; Disease Progression; Dose; Drug Kinetics; Eicosanoids; Financial Support; Flavonoids; Goals; Hepatocyte; Human; Huntington Disease; Immune; Immune response; Immune system; In Vitro; Inflammatory; Institutes; Intellectual Property; Ischemic Stroke; Laboratories; Learning; Legal patent; Lipoxygenase; Memory; Memory impairment; Microglia; Micronucleus Tests; Modeling; Molecular Target; Mus; Natural Products; Nature; Neurodegenerative Disorders; Neurons; Oral; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Play; Procedures; Process; Property; Prostaglandin-Endoperoxide Synthase; Proteomics; Research; Rheumatoid Arthritis; Risk; Risk Factors; Rodent Model; Role; Series; Testing; Therapeutic Effect; Therapeutic Intervention; Time; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; age related; aged; base; brain cell; chemical property; cognitive function; disease phenotype; drug candidate; drug discovery; exposed human population; fisetin; fly; genotoxicity; in vivo; macrophage; mouse model; nervous system disorder; neuroinflammation; novel; phase 1 study; prevent; programs; public health relevance

 DESCRIPTION (provided by applicant): There are currently no drugs or other therapeutic interventions that can reverse or halt the progression of Alzheimer's disease (AD). Age is by far the greatest risk factor for AD, and it is known from studies in both mice and humans that neuroinflammation is increased with old age and to an even greater extent in AD. Therefore, a drug that could reduce neuroinflammation and at the same time be neuroprotective would have an excellent chance in the clinic. To address this problem, we have devised a drug discovery program based upon a unique set of phenotypic screens for the toxicities to cortical neurons that occur with old age in combination with assays of anti-inflammatory activity. Our initial studies using this approach led to the identification of a molecule that modulates neuroinflammation in ways that are beneficial for altering AD progression. This is the flavonoid fisetin which our cell and animal studies have demonstrated inhibits multiple pro-inflammatory pathways. Fisetin, a rare natural flavonoid, was initially identified in the Maher laboratory as an orally active, novel neuroprotective and cognition-enhancing molecule. Fisetin protects nerve cells from multiple toxic insults and is therapeutically active in rigorous rodent models for memory, rabbit and mouse models for ischemic stroke, mouse and fly models of Huntington's disease and in transgenic AD mice. A series of much more potent fisetin derivatives, many of which maintain in vitro anti-inflammatory activity, was synthesized by SAR- driven iterative chemistry. Importantly, the derivatives do not suffer from the intellectual property challenges of the natural product fisetin and are covered under several pending patents held by the Salk Institute. From the 160 derivatives synthesized, we selected the best seven derivatives that maintain the biological activities of fisetin, including its anti-inflammatory activity, and furthe screened them in multiple assays relevant to neuroinflammation. In addition, pharmacokinetic studies were done to identify the derivatives with the best oral bioavailability and brain penetrance. Based on these studies, the best two derivatives were then tested in a stringent reversal paradigm in old symptomatic AD mice where CMS121 was found to be effective at reversing the AD phenotype. We now propose to advance CMS121 as a modulator of neuroinflammation and a clinical candidate for the treatment of AD. Specifically, we plan to (1) Test CMS121 in a novel model of old age- associated sporadic AD that accounts for 99% of the cases looking at both behavioral and biochemical changes with a focus on neuroinflammation; (2) Identify the biological target(s) of CMS121 and (3) Identify the key metabolites of CMS121 and conduct preliminary toxicology studies. The overall goal of the research described in this application is to obtain sufficient information about CMS121 to limit the risk of the expensive formal toxicology study needed for IND approval as well as provide the necessary information to increase the efficiency of these studies.

 描述（由申请人提供）：目前没有药物或其他治疗干预措施可以逆转或停止阿尔茨海默病（AD）的进展。到目前为止，年龄是AD的最大风险因素，从小鼠和人类的研究中得知，神经炎症随着年龄的增长而增加，在AD中甚至更大程度上。因此，一种能够减少神经炎症并同时具有神经保护作用的药物将在临床上有很好的机会。为了解决这个问题，我们设计了一个药物发现计划，该计划基于一组独特的表型筛选，用于与抗炎活性测定相结合的对老年发生的皮质神经元的毒性。我们使用这种方法进行的初步研究鉴定了一种分子，该分子以有利于改变AD进展的方式调节神经炎症。这是类黄酮非瑟酮，我们的细胞和动物研究表明，它抑制多种促炎途径。非瑟酮是一种罕见的天然黄酮类化合物，最初在马赫实验室被鉴定为 口服活性的新型神经保护和认知增强分子。非瑟酮保护神经细胞免受多种毒性损伤，并且在记忆的严格啮齿动物模型、缺血性中风的兔和小鼠模型、亨廷顿病的小鼠和苍蝇模型以及转基因AD小鼠中具有治疗活性。通过SAR驱动的迭代化学合成了一系列更有效的非瑟酮衍生物，其中许多保持体外抗炎活性。重要的是，这些衍生物不会受到天然产品非瑟酮的知识产权挑战，并且涵盖在索尔克研究所持有的几项未决专利之下。从合成的160个衍生物中，我们选择了最好的7个保持非瑟酮生物活性的衍生物，包括其抗炎活性，并进一步在与神经炎症相关的多个测定中筛选它们。此外，还进行了药代动力学研究，以确定具有最佳口服生物利用度和脑清除率的衍生物。基于这些研究，然后在老年症状性AD小鼠中以严格的逆转范例测试最好的两种衍生物，其中发现CMS 121有效逆转AD表型。我们现在建议将CMS 121作为神经炎症的调节剂和治疗AD的临床候选药物。具体而言，我们计划（1）在老年相关散发性AD的新模型中测试CMS 121，该模型占观察行为和生化变化的病例的99%，重点关注神经炎症;（2）鉴定CMS 121的生物靶标;（3）鉴定CMS 121的关键代谢物并进行初步毒理学研究。本申请中描述的研究的总体目标是获得关于CMS 121的足够信息，以限制IND批准所需的昂贵的正式毒理学研究的风险，并提供必要的信息以提高这些研究的效率。