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

优化小分子脂氧素模拟 FPR2 激动剂用于治疗阿尔茨海默病

• 批准号: 10255973
• 负责人: Kevin John Gaffney
• 金额: $ 44.99万
• 依托单位: RISERX LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255973
• 关键词: Acute; Affect; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Anti-Inflammatory Agents; Back; Bioavailable; Biological Assay; Brain; CD59 Antigen; Cerebrospinal Fluid; Chronic; Clinical Data; Collaborations; Deposition; Development; Disease; Dose; Ensure; Etiology; FPR2 gene; Failure; Generations; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Innovative Therapy; Interleukin-10; Intervention; Isomerism; Laboratories; Lead; Leukotriene B4; Leukotrienes; Lipids; Lipoxins; Measures; Metabolic; Metabolic dysfunction; Microglia; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurologic; Neurons; Oral; Oxidative Stress; Pathology; Performance; Permeability; Pharmaceutical Chemistry; Pharmacology; Phase; Physiological; Property; Prostaglandins; Proteins; Research; Resolution; Risk; Role; Safety; Senile Plaques; Signal Transduction; Small Business Innovation Research Grant; Strategic Planning; Testing; Translational Research; Treatment Efficacy; Work; aged; amyloid pathology; analog; base; chemical stability; cognitive function; cognitive performance; commercialization; comparative efficacy; cytokine; drug development; fatty acid metabolism; improved; in vivo; individual patient; lead series; lipoxin A4; mental state; mild cognitive impairment; mimetics; mouse model; neuroinflammation; neuron loss; new therapeutic target; novel therapeutics; pre-clinical; preclinical efficacy; prevent; research clinical testing; response; small molecule; tau Proteins

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.

抽象的 尽管有巨大的影响，但阿尔茨海默氏病（AD）的新疗法的发展仍遭受。 因此，任何状态的最高失败率。 除了Aβ沉积和神经纤维缠结，迫切需要AD的目标。 是AD的主要标志。 细胞因子和氧化应激最终导致神经元死亡，神经变性，最终，最终导致 认知能力下降。 不幸的是，脂质代谢物（SPMS）（例如，脂毒素，分辨率，男性和保护素）。 为了产生SPMS，导致促脂质脂质的脂质脂质不平衡 促炎白三烯B4（LTB4）的大脑水平明显更高，并且水平明显较低 与健康的老年人相比 个人。 这些脂质的治疗剂遭受了代谢和化学稳定性问题以及合成的疾病性。 为了克服缺点，我们开始易于合成且稳定的小分子LXA4-- 模仿FPR2激动剂。 优化由于其与LXA4相当的效力，其易于的5步合成及其物理化学特性 根据我们的初步结果和15-EPI-LXA4的临床效力，适用于CNS。 模型，我们假设Rise-103可以被优化为Oral的可饮和脑术治疗，而 维持其LXA4模仿动作。 可生物利用和CNS-PENETRANT LXA4模拟FPR2激动剂和2。 和使用小胶质细胞测定和AD鼠标模型的备份。 316开发和评估疗法以“缓慢和逆转” AD和NIA战略计划的过程 转化目标以支持创新疗法的发展AD/ADRD。