Optimizing Small Molecule Lipoxin-Mimicking FPR2 Agonists for the Treatment of Alzheimers Disease

摘要 尽管付出了巨大的努力，阿尔茨海默病(AD)的新疗法的开发仍然受到 失败率是所有疾病状态中最高的。因此，新疗法的确定为新的治疗方法 AD的目标是迫切需要的。除了Aβ沉积和神经原纤维缠结，神经炎 是AD的一个主要标志。阿尔茨海默病患者的慢性神经炎导致促炎因子水平升高 细胞因子和氧化应激，最终导致神经元死亡，神经变性，最终， 认知能力下降。在正常的生理条件下，炎症可以通过专门的前分解来解决。 脂类代谢物(SPM)(如脂氧素、解析剂、乳脂素和保护素)。不幸的是，随着年龄的增长，我们的能力 产生SPM的数量减少，导致促炎和抗炎脂质之间的失衡。AD患者 大脑中促炎症的白三烯B4(LTB4)水平显著升高，而大脑中的白三烯B4水平显著降低 健康老年人海马区和脑脊液中脂氧合酶A4的变化 个人。虽然关于LXA4和15-epi-LXA4的临床前数据为它们用作AD提供了令人信服的理由 治疗方面，这些脂类存在代谢和化学稳定性问题以及合成难易。按顺序 为了克服这些缺点，我们着手开发易于合成和稳定的小分子LXA4- 模拟FPR2激动剂。通过这些努力，Rise-103被确定为一个有希望的起点 由于其效价可与LXA4相媲美、其简单的五步合成以及其理化性质而进行的优化 适用于中枢神经系统送货。基于我们的初步结果和15-epi-LXA4治疗AD的临床前疗效 模型中，我们假设Rise-103可以优化为口服剂量和脑渗透治疗，而 保持其LXA4模拟动作。该SBIR的目标是：1.将RISE-103优化为口服 生物利用型和中枢神经系统穿透性类LXA4-FPR2激动剂和2.选择先导类LXA4-FPR2激动剂 &用小胶质细胞分析和AD小鼠模型进行备份。这里提出的研究是对PAS-19的回应- 316开发和评估“减缓和/或逆转”阿尔茨海默病病程的治疗方法和NIA战略计划 支持开发治疗AD/ADRD的创新疗法的翻译目标。

ABSTRACT Despite tremendous efforts, the development of new therapeutics for Alzheimer’s disease (AD) suffers from the highest failure rates of any disease state. As a result, the identification of novel therapies for novel therapeutic targets for AD is desperately needed. In addition to Aβ deposits and neurofibrillary tangles, neuroinflammation is a major hallmark of AD. Chronic neuroinflammation in AD leads to elevated levels of pro-inflammatory cytokines and oxidative stress which ultimately results in neuronal death, neurodegeneration, and, ultimately, cognitive decline. Under normal physiological conditions, inflammation is resolved by specialized pro-resolving lipid metabolites (SPMs) (e.g. lipoxins, resolvins, maresins, and protectins). Unfortunately, with age, our capacity to produce SPMs decreases leading to an imbalance between pro- and anti-inflammatory lipids. AD patients have significantly higher brain levels of the pro-inflammatory leukotriene B4 (LTB4) and significantly lower levels of the pro-resolving lipoxin A4 (LXA4) in the hippocampus and cerebral spinal fluid as compared to healthy aged individuals. While the pre-clinical data on LXA4 and 15-epi-LXA4 make a compelling case for their use as AD therapeutics, these lipids suffer from metabolic and chemical stability issues and synthetic intractability. In order to overcome these shortcomings, we set out to develop readily synthesizable and stable small molecule LXA4- mimicking FPR2 agonists. From these efforts, RISE-103 was identified as a promising starting point for optimization due to its comparable potency to LXA4, its facile 5-step synthesis, and its physicochemical properties suitable for CNS delivery. Based on our preliminary results and the pre-clinical efficacy of 15-epi-LXA4 in AD models, we hypothesize that RISE-103 can be optimized into an orally dosable and brain penetrant therapy while maintaining its LXA4 mimicking actions. The aims of this SBIR are: 1. To optimize RISE-103 into an orally bioavailable & CNS-penetrant LXA4-mimicking FPR2 agonist and 2. Select lead LXA4-mimicking FPR2 agonist & backup using microglia assays & an AD mouse model. Research proposed herein is in response to PAS-19- 316 to develop and evaluate therapies to “slow and/or reverse” the course of AD and the NIA Strategic Plan translational objectives to support the development of innovative therapies to treat AD/ADRD.