Next Generation Drugs for Bipolar Depression and Maintenance

项目摘要 该计划的目标是发现治疗双相抑郁的下一代药物，并 维持性(BPD)，一种影响约600万美国成年人的大脑疾病。现有的药物类别为 在过去的25年里，开发的新的行动模式(MOA)相对无效，而且很少。 这在一定程度上是由于缺乏预见性的临床前bpd疾病模型和生物制药行业的关注。 给单分子靶标下药。我们的科学前提是将发现一流的药物 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类型 以及与BPD有关的前脑回路的体外成像。我们成功地利用了这个目标- 发现和优化治疗精神疾病的新临床药物的不可知性战略：一种目前处于阶段 两项针对精神分裂症的试验，另一项正在进行第一阶段的临床试验。我们成立了蓝橡树制药公司 以进一步推进这一研究范式，并发现治疗BPD的下一代药物。 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特权化学类型库。我们将利用SmartCube？技术来生成深度行为 现有BPD药物/组合的概况。我们的新型候选特权化学类型库， 设计为CNS活性和类药物的，也将进行筛选，以确定与参考BPD类似的图谱 毒品。目标2：绘制大脑回路活动图，以确定铅化学类型的优先顺序。一种具有新型金属氧化物避雷器的铅化学类型 被选择在现有BPD药物的已知分子靶点上不起作用但可调节 中脑边缘/中皮质多巴胺、谷氨酸和GABA能通路。目标3：优化临床 候选人(S)。临床候选人(S)将通过最大化体内疗效、优化ADME特性来实现 和建立知识产权。转化医学的一个重要目标是识别出 增强脑电伽马功率作为生物标记物用于第一阶段临床研究。 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”模式 在过去的10年里发展起来的。这支世界级的团队包括了蓝橡树公司的专家--《猎毒者》 系统神经生物学、药物化学和信息学。我们将通过以下方式支持我们的研究战略 在行为分析、合成化学和大脑方面拥有尖端技术的成熟合作伙伴 成像。我们的临床和商业顾问在药物开发和 商业化。这一计划将产生几条改变大脑疾病治疗方法的途径： ·BPD临床候选人(S)，拥有转化医学生物标记物和改进的安全性、疗效特征。 ·用于确定细胞途径和参与BPD的新靶点的药理学工具(S)。 ·具有特权的化学类型和行为分析数据库，可为 针对其他大脑疾病的额外药物发现计划。

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.