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.

抑郁症是一种常见的精神障碍，可以是慢性的或反复发作的，明显损害了抑郁症患者会感到空虚、悲伤、无助，他们可能会感到不安、绝望、焦虑、毫无价值、内疚、易怒、羞愧或自杀。他们表现出食欲障碍、注意力不集中、记忆力障碍。研究还表明，健康人可能会表现出亚临床水平的症状。由于抑郁症状对社会的影响和普遍存在，抑郁症。近 20% 的人口表现出类似抑郁症的症状，是一个重大的公共卫生问题。目前，全世界有 3.5 亿人，其中 1600 万人曾出现过症状。美国有多少人受抑郁症影响，受抑郁症影响的人口范围是抗抑郁药的市场规模预计为 145.1 亿美元，并将增长至 16.8 美元。到 2020 年，这一数字将达到 10 亿。尽管最近在病理生理学假设（例如改变）方面取得了进展在神经可塑性、神经发生和神经免疫调节方面，目前的治疗缺乏快速临床疗效限制了例如为自杀患者提供所需的即时缓解的能力。因此，需要快速治疗抑郁症。睡眠剥夺激活的腺苷信号通路在临床前显示出快速的益处特别是，睡眠剥夺会上调小鼠的腺苷 A1 受体 (A1R)。 Jacobson 博士和他的团队已经鉴定出一种化合物 MRS5474 是一种有效的小分子化合物。分子 A1R 激动剂，具有特殊的药物样特性，代谢稳定，口服生物利用度高。并且在小鼠中具有出色的安全性。我们的合作者 Biber 博士表明，A1R 基因敲除小鼠表现出抑郁样症状增加相比之下，他对睡眠不足的抗抑郁作用有抵抗力。 A1R 的上调显着增强了对抑郁症的急性和慢性恢复能力此外，他们还表明，homer1a 的表达增加是一个因素。介导不同抗抑郁治疗的抗抑郁作用的最终共同途径包括 A1R 激动剂 A1R 激动剂 MRS5474 在动物中诱导快速抗抑郁作用。腹膜内（IP）给药的转基因小鼠模型。综上所述，MRS5474 具有成为快速、有效、安全的抗抑郁药的巨大潜力， Homer1a 和 ERK1,2 的表达将作为生物标志物。临床前和临床研究。在此快速通道提案中，我们将首先确定 1) MRS5474 具有良好的 BBB 穿透力（脑/血浆比率 ≥ 1），2）MRS5474 暴露与对 Homer1a 影响之间的直接关系表达水平和 ERK 活性，3) MRS5474 在口服 CDM 中的 A1R 抗抑郁作用管理和 4) 出色的安全性在第二阶段，我们将继续进行 IND 支持。研究以确保 MRS5474 具有成为成功抗抑郁药物的所有属性，并且将提交临床试验IND申请。