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障碍，可以是慢性的，也可以是反复发作的，显著损害 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、没用、内疚、易怒、羞愧或有自杀倾向。他们可能会对此失去兴趣 日常工作或体力活动。他们表现出食欲障碍，注意力不集中，记忆力不好 细节或做决定。研究还表明，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普遍流行，抑郁 症状是一个重大的公共卫生问题。近20%的人表现出类似抑郁症的症状 在他们生命中的某个阶段出现症状。目前，全球有3.5亿人，1600万人 在美国受抑郁症影响的人，受抑郁症影响的人口范围是 逐渐扩大。据估计，抗抑郁药的市场规模为145.1亿美元，并将增长至16.8美元 到2020年将达到10亿美元。尽管最近在病理生理假说方面取得了进展，如改变 在神经可塑性、神经发生和神经免疫调节方面，目前的治疗方法缺乏快速 例如，临床疗效限制了自杀患者立即缓解所需的能力。 因此，有必要对抑郁症进行快速治疗。 睡眠剥夺激活的腺苷信号通路在临床前表现出迅速的益处 和临床研究。特别是，睡眠剥夺会上调小鼠的腺苷A1受体(A1R) 和人类。雅各布森博士和他的团队已经确定一种化合物MRS5474是一种有效的小分子- 分子A1R激动剂，具有特殊的类药物特性。代谢稳定，口服生物利用度高 在小鼠身上有很好的安全性。 我们的合作者比伯博士已经证明，A1R基因敲除小鼠表现出更多的抑郁样 并对睡眠剥夺的抗抑郁作用产生抵抗力。相比之下，他 证明A1R的上调对抑郁有显著的急性和慢性弹性- 比如在各种测试中的行为。此外，他们还表明，Homer1a的表达增加是一种 不同抗抑郁药物治疗抗抑郁作用的最终共同途径 包括A1R激动剂。A1R激动剂MRS5474对动物的快速抗抑郁作用 转基因小鼠腹腔注射模型的建立。 综上所述，MRS5474具有作为一种快速、有效、安全的抗抑郁药物的巨大潜力 独特的作用机制。Hmer 1a和ERK1，2的表达可作为肿瘤标志物 临床前和临床研究。 在这份快速通道提案中，我们将首先确定1)MRS5474具有良好的血脑屏障渗透率 (脑/血浆比≥1)，2)MRS5474暴露与对Hmer 1a影响的直接关系 3)MRS5474的抗抑郁作用 管理和4)极佳的安全状况。在第二阶段，我们将继续启用IND 研究确保MRS5474具备成为成功的抗抑郁药物的所有属性，并 将提交IND申请进行临床试验。