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: 9797678
• 负责人: Janak K Padia
• 金额: $ 80.75万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797678
• 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; Penetration; 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; 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。患有抑郁症的人会感到空虚，悲伤，无助， 不安，绝望，焦虑，毫无价值，有罪，烦躁，羞愧或自杀。他们可能对 常规工作或体育活动。他们表现出食欲障碍，集中问题，记住 详细信息或做出决定。还显示，健康的人可能表现出次临床水平 抑郁症状。由于它们对社会的影响和宽敞的流行率，抑郁症 症状是一个重大的公共卫生问题。近20％的人口显示出抑郁症状 在他们生活的某个时候症状。目前，全球有3.5亿人，1600万人 在美国受抑郁影响以及受抑郁影响的人口范围的人是 逐渐扩展。抗抑郁药的估计市场为145.1亿美元，将增长至16.8美元 到2020年，十亿美元。尽管病理生理假设最近取得了进步，例如改变 在神经塑性，神经发生和神经免疫学调节中，目前的治疗缺乏快速 例如，临床效率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。 通过睡眠剥夺激活的腺苷信号通路已显示出临床前的快速益处 和临床研究。特别是，睡眠剥夺上调小鼠腺苷A1受体（A1R） 和人类。雅各布森博士及其小组已经确定了一个化合物MRS5474是潜在的小型 分子A1R激动剂具有特殊的药物样性能。它是代谢稳定的，口头生物利用的 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淘汰小鼠暴露了抑郁症的较高 行为，对睡眠剥夺的抗抑郁作用有抵抗力。相反，他 证明A1R的上调对抑郁症的急性和慢性韧性 - 在各种测试中都喜欢行为。此外，他们还表明，Homer1a的表达增加是一个 最终的公共途径介导不同抗抑郁药的抗抑郁作用 包括A1R激动剂。 A1R激动剂MRS5474在动物中诱导了快速抗抑郁作用 具有腹膜内（IP）给药的转基因小鼠的模型。 总而言之，MRS5474具有巨大的潜力，可以成为一种快速，高效和安全的抗抑郁药 独特的作用机制。 HOMER1A和ERK1,2的表达将作为生物标志物 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）出色的安全性。在第二阶段，我们将继续启用 研究以确保MRS5474具有成为成功抗抑郁药的所有属性，并且 将提交IND申请进行临床试验。