Development of EP2 receptor antagonists for suppression of Alzheimer's neuropathology

层级摘要 阿尔茨海默病(AD)是一种神经退行性疾病，是导致老年人痴呆的主要原因。广告通向 认知功能的进行性丧失。目前，约有540万美国人(65岁及以上人口中每8人中就有1人)还活着 随着AD的出现，这一数字预计到2050年将增加两倍。每年约有2000亿美元用于所有 护理AD患者的各个方面，但目前还没有明显改变疾病进展和治疗的治疗方法 不可避免的认知能力下降。基于淀粉样蛋白级联假说的小分子药物 到目前为止还没有显示出明显的临床益处。因此，重视新药的鉴定就显得尤为重要。 靶点和小分子通过新的生物作用模式为未来的AD治疗发挥作用。 COX-2水平在AD早期升高，其水平与A-肽水平呈正相关。临床 研究表明，如果在阿尔茨海默病的无症状阶段给予COX-2抑制剂，对预防AD可能是有用的 这种疾病，但它们可能对临床诊断为认知障碍的患者几乎没有好处。然而， 长期使用COX-2药物(例如万络和百特)会导致不良心血管事件，这令人担忧 对于已经有更高心脏病风险的AD患者。因此，未来在患者身上使用COX-2药物将 是有限的。COX-2催化合成五种前列腺素：PGD2、PGE2、PGF2、PGI2和TxA2， 它们分别激活11种前列腺素受体Dp1、DP2、EP1、EP2、EP3、EP4、FPα，、IP和TPα，。我们 假设靶向EP2，COX-2下游的一种特定的前列腺素受体，而不是 完整的COX-2信号转导是使用EP2特异性拮抗剂治疗AD的一种更好的治疗策略。在这项研究中，我们 建议开发一种EP2选择性拮抗剂，以证明EP2拮抗剂是否抑制 5XFAD模型的炎症、神经退行性变和认知功能障碍，并建立初步的安全性 可能在AD患者上使用EP2药物的包。

Lay Summary Alzheimer's disease (AD), a neurodegenerative disorder, is a leading cause of dementia in elderly. AD leads to progressive loss of cognitive functions. Currently about 5.4 million Americans (1 in 8 persons 65 or older) are living with AD, and the number is expected to triple by the year 2050. Approximately $200 billion per year is spent on all aspects of caring for AD patients, yet there is no therapy on the horizon that clearly alters the disease progression and inevitable cognitive decline. The small molecule drugs that have been developed based on amyloid cascade hypothesis have not shown a clear clinical benefit so far. Thus it would be very important to focus on identification of novel drug targets and small molecules that work through novel mode of biological action for future AD therapy. COX-2 levels are increased at the early stage of AD, and its levels are correlated with levels of A-peptides. Clinical studies suggest that COX-2 inhibitors may be useful as preventative for AD if they were given at asymptomatic stage of the disease, but they may offer little or no benefit to clinically diagnosed patients with cognitive deficits. However, chronic use of COX-2 drugs (examples, Vioxx and Bextra) resulted in adverse cardiovascular events, which is worrying for the AD patients who already are at increased risk for heart disease. Thus, future use of COX-2 drugs on patients will be limited. COX-2 catalyzes the first-step towards synthesis of five prostaglandins; PGD2, PGE2, PGF2, PGI2, and TxA2, which activate eleven prostanoid receptors, DP1, DP2, EP1, EP2, EP3, EP4, FPα, , IP and TPα,  respectively. We hypothesize that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the entire COX-2 signaling is a superior therapeutic strategy for AD with an EP2 specific antagonist. In this study, we propose to develop an EP2 selective antagonist, to demonstrate a proof of concept whether EP2 antagonist suppresses inflammation, neurodegeneration and cognitive deficits in 5XFAD model of AD, and to establish a preliminary safety package for using EP2 drugs potentially on AD patients.