Next Generation Drugs for Bipolar Depression and Maintenance

治疗双相抑郁症和维持治疗的下一代药物

• 批准号: 9555300
• 负责人: Thomas H Large
• 金额: $ 44.94万
• 依托单位: BLUE OAK PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9555300
• 关键词: Adult; Affect; American; Back; Behavioral; Biological Assay; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain; Brain Diseases; Brain Mapping; Brain imaging; Businesses; Chemistry; Clinical; Clinical Research; Custom; Databases; Deoxyglucose; Disease model; Dopamine; Dose; Drug Combinations; Drug Screening; Economic Burden; Electroencephalography; Ensure; Excretory function; FOS gene; Future; Glutamates; Goals; Human; Immediate-Early Genes; In Vitro; Industry; Informatics; Intellectual Property; Lead; Libraries; Maintenance; Maps; Medical; Mental disorders; Metabolism; Methods; Modeling; Molecular Target; Moods; National Institute of Mental Health; Neurobiology; Neurotransmitters; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Positioning Attribute; Primates; Property; Prosencephalon; Psychotic Disorders; Psychotropic Drugs; Records; Research; Rodent; Safety; Schizophrenia; Synthesis Chemistry; System; Technology; Testing; Therapeutic; absorption; base; clinical candidate; commercialization; design; drug development; drug discovery; drug maintenance; ex vivo imaging; improved; in vivo; lead optimization; network models; neurochemistry; next generation; novel; novel therapeutics; pre-clinical; programs; screening program; social; tool; translational medicine

Project Summary The goal of this program is to discover the next generation of drugs for bipolar depression and maintenance (BPD), a brain disorder that affects ~6 million adult Americans. Existing drug classes are relatively ineffective and very few new modes-of-action (MOAs) have been developed in the past 25+ years. This is due, in part, to the lack of predictive preclinical BPD disease models and the biopharma industry focus on drugging single molecular targets. Our scientific premise is that first-in-class drugs will be discovered by testing novel, custom-designed privileged chemotypes using a proven behavioral profiling method and ex vivo imaging of the forebrain circuits implicated in BPD. We successfully employed this target- agnostic strategy to discover and optimize novel clinical drugs for psychiatric illness: one is currently in Phase 2 trials for schizophrenia and another is in Phase 1 clinical trials. We founded Blue Oak Pharmaceuticals in order to further advance this research paradigm and discover the next generation of drugs for BPD. Our research plan: Aim 1: Develop a “behavioral map” for BPD reference drugs and screen the Blue Oak privileged chemotype library. We will utilize the SmartCubeâ technology to generate deep behavioral profiles of the existing BPD drugs/combinations. Our library of novel candidate privileged chemotypes, designed to be CNS active and drug-like, will also be screened to identify profiles similar to the reference BPD drugs. Aim 2: Map brain circuit activity to prioritize lead chemotypes. A lead chemotype with a novel MOA will be selected that is inactive at known molecular targets for existing BPD drugs but modulates mesolimbic/mesocortical dopamine, glutamate and GABAergic pathways. Aim 3: Optimize clinical candidate(s). Clinical candidate(s) will be achieved by maximizing in vivo efficacy, optimizing ADME properties and establishing intellectual property. An important translational medicine goal is to identify compounds that enhance EEG gamma power as a biomarker for use in Phase 1 clinical studies. To execute this program effectively, we will utilize the “research network” model that we have developed over the past 10 years. This world-class team includes Blue Oak “drug hunters” who are experts in systems neurobiology, medicinal chemistry and informatics. We will enable our research strategy with established partners that have cutting edge technologies in behavioral profiling, synthetic chemistry and brain imaging. Our clinical and business advisors have proven track records in drug development and commercialization. This program will generate several paths that transform therapeutics for brain disorders: · BPD clinical candidate(s) with translational medicine biomarkers and improved safety, efficacy profiles. · Pharmacological tools for identifying cellular pathways and novel target(s) involved in BPD. · Privileged chemotypes and a behavioral profiling database that provides excellent starting points for additional drug discovery programs for other brain disorders.

项目摘要 该计划的目的是发现下一代躁郁症抑郁症和 维护（BPD），一种影响约600万成年美国人的脑部疾病。现有的药物类是 在过去的25年以上，已经开发出相关的无效和很少的新作用模式（MOA）。 这部分是由于缺乏预测性临床前BPD疾病模型和生物制药行业的重点 在吸毒单分子靶标。我们的科学前提是将发现一流的药物 通过测试新颖，定制设计的特权化学型，使用经过验证的行为分析方法 以及BPD中实现的前脑电路的体内成像。我们成功实现了这个目标 - 发现和优化精神病的新型临床药物的不可知论策略：目前正在阶段 2次精神分裂症和另一个试验是在第1阶段临床试验中。我们在 为了进一步推进这项研究范式并发现BPD的下一代药物。 我们的研究计划：目标1：为BPD参考药物开发“行为图”，并筛选蓝色 橡木特权化学型库。我们将利用SmartCube技术来产生深厚的行为 现有BPD药物/组合的概况。我们的新颖候选人库特权化学型， 设计为CNS活跃和类似药物，也将被筛选以识别类似于参考BPD的轮廓 毒品。 AIM 2：地图脑电路活性以优先考虑铅化学型。具有新型MOA的铅化学型将 选择现有BPD药物的已知分子靶标的无活性但调节 中唇/中皮层多巴胺，谷氨酸和GABA能途径。目标3：优化临床 候选人。临床候选者将通过最大化体内效率来实现，优化ADME特性 并建立知识产权。一个重要的转化医学目标是识别化合物 增强EEG伽马功率作为1阶段临床研究中使用的生物标志物。 为了有效地执行此程序，我们将利用我们拥有的“研究网络”模型 在过去的十年中发展。这个世界一流的团队包括专家的蓝橡树“毒品猎人” 在系统神经生物学，医学化学和信息方面。我们将通过 在行为分析，合成化学和大脑方面具有尖端技术的成熟伙伴 成像。我们的临床和业务顾问在药物开发方面已有验证记录和 商业化。该程序将产生几条途径，使脑部疾病的治疗疗法： ·BPD临床候选者，具有转化医学生物标志物和提高安全性，效率概况。 ·用于识别BPD涉及的细胞途径和新靶标的药理工具。 ·特权化学型和行为概况数据库，该数据库为 其他脑疾病的其他药物发现计划。