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

• 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
• 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

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疾病，可以是慢性的或反复发作的， 一个人在正常生活中的能力。抑郁症患者会感到空虚、悲伤、无助， 不安、绝望、焦虑、无用、内疚、易怒、羞愧或自杀。他们可能会失去兴趣， 日常工作或体力活动。他们表现出食欲不振，注意力不集中，记忆力不好 细节或决策。还表明，健康人可能表现出亚临床水平的 抑郁症状由于其对社会的影响和广泛流行，抑郁症 症状是一个重要的公共卫生问题。近20%的人，表现出抑郁样 在他们生命中的某个阶段出现症状。目前，全球有3.5亿人， 受抑郁症影响的美国人，受抑郁症影响的人口范围是 逐渐扩大。抗抑郁药的估计市场为145.1亿美元，并将增长到16.8亿美元。 到2020年，尽管最近在病理生理学假设方面取得了进展， 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的 临床疗效限制了例如自杀患者所需的即时缓解的能力。 因此，需要快速治疗抑郁症。 由睡眠剥夺激活的腺苷信号通路在临床前研究中显示出快速的益处。 和临床研究。特别是，睡眠剥夺上调小鼠的腺苷A1受体（A1 R 还有人类雅各布森博士和他的小组已经确定了一种化合物MRS 5474作为一种有效的小- 分子A1 R激动剂具有特殊的药物样性质。它是代谢稳定，口服生物利用度 并且在小鼠中具有极好的安全性。 我们的合作者，Biber博士，已经表明A1 R基因敲除小鼠表现出增加的抑郁样 行为和抵抗睡眠剥夺的抗抑郁作用。相反，他 表明A1 R的上调对抑郁症具有明显的急性和慢性恢复力， 在各种测试中的表现。此外，他们还表明，homer 1a表达的增加是一个重要因素。 介导不同抗抑郁治疗的抗抑郁作用的最终共同途径 包括A1 R激动剂A1受体激动剂MRS 5474在动物中诱导快速的抗抑郁作用 腹膜内（IP）给药的转基因小鼠模型。 总之，MRS 5474具有成为快速、有效和安全的抗抑郁药的巨大潜力， 独特的作用机制。Homer 1a和ERK 1，2的表达将作为生物标志物， 临床前和临床研究。 在本快速通道提案中，我们将首先确定1）MRS 5474具有良好的BBB渗透性 （脑/血浆比值≥ 1），2）MRS 5474暴露与对Homer 1a的影响之间存在直接关系 表达水平和ERK活性，3）MRS 5474在CDM中的A1 R抗抑郁作用， 4）良好的安全性。在第二阶段，我们将继续支持IND 研究，以确保MRS 5474具有成为成功的抗抑郁药的所有属性， 将提交IND临床试验申请。