Development of mGIuR5 NAMS for Treatment of Major Depression

用于治疗重度抑郁症的 mGIuR5 NAMS 的开发

• 批准号: 8603872
• 负责人: P Jeffrey Conn
• 金额: $ 120.61万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-08 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603872
• 关键词: Affect; American; Animal Model; Animals; Behavioral; Clinical; Clinical Research; Development; Disease remission; Equilibrium; Future; Lead; Major Depressive Disorder; Metabotropic Glutamate Receptors; Neurosciences; Patients; Pharmaceutical Preparations; Property; Refractory; Symptoms; Validation; base; disability; drug discovery; experience; novel; novel strategies; novel therapeutics; pre-clinical; public health relevance; scaffold; translational study

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) affects approximately 16% of Americans and represents one of the most common causes of disability worldwide. Unfortunately, less than one third of patients experience sustained remission of MDD symptoms with currently available medications. Recent studies have raised the exciting possibility that highly selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate receptor mGlus subtype may provide a novel approach to the treatment of MDD. This mechanism represents a fundamental departure from existing therapies and has the potential to provide more rapid onset than existing therapies and may provide sustained relief for refractory patients. In this revised NCDDG application, we propose studies aimed at using our novel mGlus NAMs discovered at the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) to further validate this mechanism in animal models and perform translational studies that can support a future clinical development effort. In addition, we will optimize novel mGlus NAMs to achieve properties required to select a lead clinical development candidate and backup compounds. This will require coordinated efforts of two major projects and support of 2 cores. Project 1 will focus on animal studies aimed at further characterizing the behavioral effects and CNS occupancy of novel mGlus NAMs. In Project 2, we will chemically optimize novel mGlus NAMs based on this scaffold to achieve a balance of properties required to select a clinical development candidate that can advance to IND-enabling studies and clinical development. These projects will be supported by two cores, including a Bioanalytical and DMPK Core (Core A) and Administrative Core (Core B).

描述（由申请人提供）：重度抑郁症 (MDD) 影响着大约 16% 的美国人，是全世界最常见的残疾原因之一。不幸的是，只有不到三分之一的患者使用目前可用的药物可以持续缓解重度抑郁症症状。最近的研究提出了一种令人兴奋的可能性，即代谢型谷氨酸受体 mGlus 亚型的高选择性拮抗剂或负变构调节剂 (NAM) 可能为 MDD 的治疗提供一种新方法。这种机制代表了与现有疗法的根本区别，并且有可能比现有疗法起效更快，并且可以为难治性患者提供持续的缓解。在这份修订后的 NCDDG 申请中，我们提出了旨在利用范德比尔特神经科学药物发现中心 (VCNDD) 发现的新型 mGlus NAM 的研究，以进一步在动物模型中验证这一机制，并进行可支持未来临床开发工作的转化研究。此外，我们将优化新型 mGlus NAM，以实现选择主要临床开发候选药物和备用化合物所需的特性。这需要两个重大项目的协同努力和两个核心的支持。项目 1 将重点关注动物研究，旨在进一步表征新型 mGlus NAM 的行为效应和 CNS 占用。在项目 2 中，我们将基于该支架对新型 mGlus NAM 进行化学优化，以实现选择可推进 IND 支持研究和临床开发的临床开发候选药物所需的特性平衡。这些项目将得到两个核心的支持，包括生物分析和 DMPK 核心（核心 A）和管理核心（核心 B）。