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 该项目的目标是发现下一代治疗双相抑郁症的药物， BPD是一种大脑疾病，影响约600万成年美国人。现有的药物类别是 在过去的25年多里，相对无效并且很少有新的作用方式（MOA）被开发出来。 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关注 对单个分子目标下药我们的科学前提是，一流的药物将被发现 通过使用经过验证的行为分析方法测试新的、定制设计的特权化学型， 以及涉及BPD的前脑回路的离体成像。我们成功地利用了这个目标- 发现和优化用于精神疾病的新型临床药物的不可知策略：一个目前处于第三阶段 2项精神分裂症试验，另一项正在进行1期临床试验。我们成立了蓝橡树制药公司， 为了进一步推进这一研究范式，并发现下一代BPD药物。 我们的研究计划：目标1：开发BPD参考药物的“行为地图”并筛选蓝色 Oak特许化学型文库。我们将利用SmartCubeTM技术生成深度行为 现有BPD药物/组合的概况。我们的新候选特权化学型库， 设计为CNS活性和药物样，也将进行筛选，以确定与参比BPD相似的特征 毒品目的2：绘制大脑回路活动图，以优先考虑铅化学类型。具有新型MOA的领先化学型将 选择对现有BPD药物的已知分子靶点无活性但调节 中脑边缘/中皮层多巴胺、谷氨酸和GABA能通路。目标3：优化临床 候选人。将通过最大化体内疗效、优化ADME特性 并建立知识产权。转化医学的一个重要目标是鉴定 增强EEG伽马功率作为生物标志物用于1期临床研究。 为了有效地执行这一计划，我们将利用我们拥有的“研究网络”模型 在过去的10年里发展起来的。这个世界级的团队包括蓝橡树“毒品猎人”谁是专家 系统神经生物学、药物化学和信息学。我们将使我们的研究战略， 在行为分析、合成化学和大脑领域拥有尖端技术的合作伙伴 显像我们的临床和业务顾问在药物开发方面有良好的记录， 商业化该计划将产生几种改变大脑疾病治疗方法的途径： ·具有转化医学生物标志物和改善的安全性、功效特征的BPD临床候选者。 ·用于鉴定BPD中涉及的细胞途径和新靶点的药理学工具。 ·标记的化学型和行为分析数据库，为以下方面提供了极好的起点： 其他脑部疾病的药物研发项目。