Development of an adenosine A1 receptors agonist, MRS5474 for the treatment of chronic depression

开发用于治疗慢性抑郁症的腺苷 A1 受体激动剂 MRS5474

基本信息

批准号：
10220705
负责人：
Janak K Padia
金额：
$ 93.5万
依托单位：
PRIMETIME LIFE SCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220705
关键词：
Acute Adenosine Adenosine A1 Receptor Adverse effects Affect Agitation Agonist Animal Model Animals Antidepressive Agents Appetite Disorder Behavior Behavioral Binding Bioavailable Biological Assay Biological Markers Blood Brain Cardiovascular system Chronic Clinical Research Clinical Trials Decision Making Deep Brain Stimulation Depressed mood Development Disease Dose Drug Exposure Drug Kinetics Ensure Exhibits Face Formulation Foundations Goals Homer 1a Human Imipramine Individual Intervention Ketamine Knockout Mice Life MAPK3 gene Mediating Medical Mental Depression Mental disorders Metabolic Metabolism Microelectrodes Modeling Molecular Mus National Institute of Diabetes and Digestive and Kidney Diseases Neuraxis Neuronal Plasticity Neurons Oral Oral Administration Pathway interactions Persons Pharmaceutical Preparations Pharmacology Phase Physical activity Plasma Play Population Pre-Clinical Model Prevalence Production Property Prosencephalon Public Health Rattus Recurrence Regulation Resistance Risk-Benefit Assessment Rodent Safety Signal Pathway Sleep Deprivation Societies Specificity Stress Sucrose Symptoms Tail Suspension Testing Therapeutic Agents Toxic effect Toxicology Transgenic Mice Transgenic Model Translating Up-Regulation Work antidepressant effect anxious base blood-brain barrier penetration brain tissue chronic depression clinical application clinical efficacy depression model depressive symptoms design efficacy study forced swim test genotoxicity heart function interest intraperitoneal mouse model neurogenesis neuroprotection overexpression patch clamp pharmacokinetics and pharmacodynamics pre-clinical preclinical development preclinical study preference receptor receptor expression resilience respiratory small molecule socioeconomics suicidal suicidal patient suicidal risk

项目摘要

Depression is a common mental disorder, which can be chronic or recurrent, markedly tarnishing a person’s ability to function in their normal life. People with a depression can feel empty, sad, helpless, restless, hopeless, anxious, worthless, guilty, irritable, ashamed or suicidal. They may lose interest in routine work or physical activities. They show appetite disorder, problems concentrating, remembering details or making decisions. It has also been shown that healthy people may exhibit sub-clinical levels of depressive symptoms. Because of their impact on the society and widespread prevalence, depressive symptoms are a significant public health concern. Nearly 20% of the population, show depression-like symptoms at some point in their lives. Currently, there are 350 million people worldwide and 16 million people in the US affected by depression, and the scope of the population affected by depression is gradually expanding. The estimated market for antidepressants was $14.51 billion and will grow to $16.8 billion by the year 2020. Despite recent advances in pathophysiological hypotheses such as alterations in neuroplasticity, neurogenesis, and neuroimmunological regulation, current treatments lack rapid clinical efficacy limiting the ability, for example, to bring instant relief needed with suicidal patients. Therefore, there is a need for the rapid treatment of depression. The adenosine signaling pathway activated by sleep deprivation has shown rapid benefits in preclinical and clinical studies. In particular, sleep deprivation upregulates adenosine A1 receptors (A1R) in mice and humans. Dr. Jacobson and his group have identified a compound MRS5474 as a potent small- molecule A1R agonist with exceptional drug-like properties. It is metabolically stable, orally bioavailable and has an excellent safety profile in mice. Our collaborator, Dr. Biber, has shown that A1R knockout mice exhibit an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation. In contrast, he demonstrated that upregulation of A1R had pronounced acute and chronic resilience toward depressive- like behavior in various tests. Furthermore, they also showed that increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments including the A1R agonist. The A1R agonist MRS5474 induced a rapid antidepressant effects in animal models of transgenic mice with intraperitoneal (IP) administration. In summary, MRS5474 has great potential to be a rapid, efficacious and safe antidepressant with a unique mechanism of action. The expression of Homer1a and ERK1,2 will serve as biomarkers for preclinical and clinical studies. In this Fast-Track proposal, we will first establish that 1) MRS5474 has good BBB penetration (Brain/Plasma ratio ≥ 1), 2) direct relationship between exposure of MRS5474 and effects on Homer1a expression levels and ERK activity, 3) A1R antidepressant effects of MRS5474 in the CDM with oral administration and 4) an excellent safety profile. In the Phase II, we will continue with IND enabling studies to ensure that MRS5474 has all the attributes to become a successful antidepressant drug and will file IND application for clinical trials.

深度是一种常见的精神障碍，可以是慢性或经常性的，显着损害了人在正常生活中发挥作用的能力。不安，绝望，焦虑，无水，有罪，烦躁，羞愧或自杀。常规工作或体育锻炼。细节或做出决定。抑郁症状。症状是一个重大的公共卫生问题。目前，全球有3.5亿人的症状美国的人们隶属于剥夺的人，而深度的人口范围是抗抑郁药的估计市场逐渐扩大，为145.1亿美元到2020年，十亿美元。尽管有病理生理假设的最近进展在神经塑料，神经发生和神经免疫学调节中，当前的信任缺乏迅速的例如，临床功效限制了自杀患者需要即时缓解能力的能力。因此，需要快速治疗抑郁症。睡眠不足激活的腺苷信号通路在临床前显示了快速的好处尤其是临床研究。和人类。具有非凡的药物样特性的分子A1R激动剂。并且在小鼠中具有出色的安全性。 OurLaborator Biber博士表明，A1R敲除小鼠的深度有所增加对比，行为对睡眠剥夺的抗抑郁作用有抵抗力证明A1R的上调对抑郁的急性和慢性韧性 - 像各种测试中的行为一样。介导抗抑郁治疗的抗抑郁作用的最终公共途径包含A1R激动剂。具有体内（IP）给药的转基因小鼠的模型。总而言之，MRS5474具有很大的潜力独特的作用机制。临床前和临床研究。在这个快速提案中，我们将首先确定1）MRS5474具有良好的BBB穿透（大脑/血浆比1），2）MRS5474暴露与Homer1a的影响之间的直接关系表达水平和ERK活性，3）MRS5474在CDM中的A1R A1R抗抑郁作用管理和4）在II阶段的出色安全性。确保MRS5474具有所有属性的研究将提交IND申请进行临床试验。