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

 描述(由申请人提供)：目前还没有药物或其他治疗干预措施可以逆转或阻止阿尔茨海默病(AD)的进展。到目前为止，年龄是阿尔茨海默病最大的危险因素，从对小鼠和人类的研究中都知道，神经炎症随着年龄的增长而增加，在阿尔茨海默病中甚至更严重。因此，一种既能减少神经炎症又能起到神经保护作用的药物将有很好的临床应用前景。为了解决这个问题，我们设计了一个药物发现计划，该计划基于一套独特的表型筛选，结合抗炎活性的分析，对老年发生的皮质神经元毒性进行筛选。我们最初使用这种方法的研究导致了一种分子的鉴定，这种分子以有利于改变AD进展的方式调节神经炎症。这就是我们的细胞和动物研究表明的类黄酮非瑟素可以抑制多种促炎途径。非瑟酮是一种罕见的天然类黄酮，最初在马赫实验室被鉴定为一种 口服活性，新型神经保护和认知增强分子。非瑟素可保护神经细胞免受多种毒性损伤，并在严格的记忆啮齿动物模型、兔和小鼠缺血性中风模型、亨廷顿病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素衍生物，其中许多在体外保持了抗炎活性。重要的是，这些衍生品不会受到天然产品鱼腥草素的知识产权挑战，并受到索尔克研究所持有的几项正在申请的专利的保护。从合成的160个衍生物中，我们选择了最好的7个保持非瑟素生物活性的衍生物，包括它的抗炎活性，并通过与神经炎症相关的多种方法对它们进行了进一步筛选。此外，还进行了药代动力学研究，以确定具有最好的口服生物利用度和脑透性的衍生物。在这些研究的基础上，然后在有症状的老年AD小鼠身上用严格的逆转范式测试了最好的两个衍生物，在那里发现CMS121在逆转AD表型方面是有效的。我们现在建议将CMS121作为神经炎症的调节剂和治疗AD的临床候选药物。具体地说，我们计划(1)在一种新的老年相关散发性AD模型中测试CMS121，该模型占观察行为和生化变化的病例的99%，重点是神经炎症；(2)确定CMS121的生物靶点(S)；(3)确定CMS121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CMS121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。

 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.