HIGH THROUGHPUT IN VIVO DRUG DISCOVERY-PHASE 1

高通量体内药物发现第一阶段

• 批准号: 6851710
• 负责人: EMER LEAHY
• 金额: $ 25万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-06 至 2006-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851710
• 关键词: antidepressants; antipsychotic agents; biotechnology; cell surface receptors; chemical structure; combinatorial chemistry; computer program /software; drug discovery /isolation; drug screening /evaluation; high throughput technology; laboratory mouse; mental disorder chemotherapy; psychopharmacology; tranquilizer

DESCRIPTION (provided by applicant): The current trend in drug discovery is to develop drugs with a high level of selectivity for a single receptor. Although this is a real improvement for certain therapeutic areas, this may present a real issue for the development of novel treatments for neurological and psychiatric disorders. Indeed, neuropsychiatric disorders are complex, multigenic disorders that involve multiple neuronal circuits. Therefore, it is not surprising that many of the most efficacious drugs in psychiatry, such as clozapine, are considered "dirty drugs" (i.e. have multiple targets), that were discovered by screening in vivo, i.e. looking at their behavioral impact using various animal models, rather than making predictions of their function based on their receptor profile. Although attractive, this approach was neither efficient nor scalable until now. PsychoGenics is developing a proprietary, high throughput, in vivo platform known as Smart Cube TM, which is being used to screen and select drug candidates with potential to treat major psychiatric disorders including depression, psychosis, and anxiety disorders. This approach examines the behavioral response of a mouse to various challenges under normal and perturbed (e.g. drug treated) conditions. Using computer vision algorithms, behavior is captured and bioinformatic tools are applied to reveal the temporal behavioral profile or "signature" in response to treatment. PsychoGenics is building a database of signatures for known and approved compounds, which it can use to compare to the profiles of NCEs. PsychoGenics aims to demonstrate that this behavior-driven approach to drug discovery can yield clinical candidates selected from high quality libraries designed with compounds that have drug-like chemical and structural properties. The goal is to screen 120 compounds in Abstract compounds in Smart CubeTM in Phase I to find "hits" which, with the aid of novel computational chemistry algorithms, undergo behavior-driven (i.e. Smart Cube TM) lead optimization in Phase II. Using this behavior-driven approach, PsychoGenics has already identified two compounds for the treatment of ADD.

描述（由申请人提供）：药物发现的当前趋势是开发对单一受体具有高水平选择性的药物。虽然这对于某些治疗领域来说是真实的改进，但这对于神经和精神疾病的新治疗的开发来说可能是真实的问题。事实上，神经精神疾病是复杂的，多基因的疾病，涉及多个神经回路。因此，许多精神病学中最有效的药物，如氯氮平，被认为是“肮脏的药物”（即具有多个靶点），这并不奇怪，这些药物是通过体内筛选发现的，即使用各种动物模型观察其行为影响，而不是根据其受体谱预测其功能。尽管这种方法很有吸引力，但到目前为止，它既不高效，也不可扩展。PsychoGenics正在开发一种专有的、高通量的、被称为Smart Cube TM的体内平台，该平台被用于筛选和选择有潜力治疗包括抑郁症、精神病和焦虑症在内的主要精神疾病的候选药物。该方法检查小鼠在正常和扰动（例如药物处理）条件下对各种挑战的行为反应。使用计算机视觉算法，捕获行为并应用生物信息学工具来揭示响应于治疗的时间行为概况或“签名”。 PsychoGenics正在为已知和批准的化合物建立一个签名数据库，它可以用来与NCE的特征进行比较。PsychoGenics旨在证明，这种行为驱动的药物发现方法可以产生从高质量库中选择的临床候选药物，这些库设计有药物样化学和结构特性的化合物。其目标是在第一阶段的Smart CubeTM中筛选抽象化合物中的120种化合物，以找到“命中”，这些化合物在新的计算化学算法的帮助下，在第二阶段进行行为驱动（即Smart CubeTM）的先导优化。使用这种行为驱动的方法，PsychoGenics已经确定了两种用于治疗ADD的化合物。