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

开发用于抑制阿尔茨海默病神经病理学的 EP2 受体拮抗剂

基本信息

批准号：
9645890
负责人：
Thota Ganesh
金额：
$ 8.3万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9645890
关键词：
APP-PS1 Ablation Acute Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Disease Models Anti-inflammatory Biological Blood - brain barrier anatomy Brain CCL2 gene Cardiovascular system Caring Cause of Death Cell Line Chronic Clinical Clinical Research Cognitive deficits Dementia Development Dinoprost Dinoprostone Disease Disease Progression Disease model Dose Drug Kinetics Elderly Enzyme-Linked Immunosorbent Assay Epilepsy Epoprostenol Event Formulation Fracture Future G-Protein-Coupled Receptors Generations Generic Drugs Gliosis Goals Half-Life Hippocampus (Brain)Histology Human Impaired cognition In Vitro Inflammation Inflammation Mediators Interleukin-1 Interleukin-1 beta Interleukin-10 Interleukin-6 Lead Mediating Medical Memory impairment Microglia Modeling Morbidity - disease rate Mus Names Nerve Degeneration Neurodegenerative Disorders Neurons Oral Oxidative Stress PTGS2 gene Parkinson Disease Pathology Patients Peptides Permeability Persons Phagocytosis Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pilocarpine Plasma Plasma Enhancement Play Property Prostaglandin D2 Prostaglandins Quantitative Reverse Transcriptase PCR Rodent Rodent Model Rofecoxib Role Route Safety Signal Transduction Solubility Stains Status Epilepticus TNF gene Testing Therapeutic Up-Regulation Valdecoxib WFDC2 gene Work aqueous base bone bone healing bone loss clinical Diagnosis cognitive function cyclooxygenase 2 heart disease risk high throughput screening in vivo Model inhibitor/antagonist knockout gene macrophage morris water maze mouse model nervous system disorder neuroinflammation neuropathology neurotoxicity new therapeutic target novel prevent receptor salt sensitive hypertension small molecule spatial memory

项目摘要

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.

摘要摘要阿尔茨海默氏病（AD）是一种神经退行性疾病，是痴呆症的主要原因。广告导致认知功能的逐渐丧失。目前约有540万美国人（65岁或65岁以上）居住使用广告，预计到2050年的数字将三倍。每年约有2000亿美元照顾广告患者的各个方面，但是没有疗法明显改变了疾病进展和不可避免的认知下降。基于淀粉样蛋白级联假设开发的小分子药物到目前为止尚未显示出明显的临床益处。专注于新药的识别将非常重要通过新颖的生物学作用模式起作用的靶标和小分子，用于未来的AD疗法。在AD的早期阶段，COX-2水平升高，其水平与A肽的水平相关。临床研究表明，如果COX-2抑制剂在无症状的阶段给出了AD的预防性该疾病，但它们可能对临床诊断的认知缺陷患者几乎没有任何好处。然而，长期使用COX-2药物（示例，Vioxx和Bextra）导致心血管不良事件，这令人担忧对于已经处于心脏病风险增加的AD患者。那就是，将来对患者的COX-2药物使用将受到限制。 COX-2催化了五个前列腺素的第一步； PGD2，PGE2，PGF2，PGI2和TXA2，激活11个前列腺素受体DP1，DP2，EP1，EP2，EP3，EP3，EP4，FPα，，IP和TPα，。我们假设靶向COX-2下游的特定前列腺素受体EP2，而不是该的通用块整个COX-2信号传导是具有EP2特异性拮抗剂的AD的优质治疗策略。在这项研究中，我们提出开发EP2选择性拮抗剂的建议，以证明EP2拮抗剂是否抑制概念证明 AD的5xFAD模型中的炎症，神经变性和认知防御，并建立初步安全性用于使用AD患者使用EP2药物的包装。