Development of mGIuR5 NAMS for Treatment of Major Depression

mGIuR5 NAMS 的开发用于治疗重度抑郁症

• 批准号: 8434427
• 负责人: P Jeffrey Conn
• 金额: $ 134.01万
• 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/8434427
• 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）影响了大约16％的美国人，并且代表了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经历了目前可用的药物缓解MDD症状。最近的研究提出了令人兴奋的可能性，即高度选择性的拮抗剂或代谢型谷氨酸受体MGLUS亚型的负变态调节剂（NAM）可能为MDD治疗提供一种新颖的方法。这种机制代表了与现有疗法的基本不同，并且有可能比现有疗法更快地发作，并可能为难治性患者提供持续的缓解。在此修订后的NCDDG应用中，我们提出了旨在使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，以进一步验证动物模型中的这种机制并进行转化研究，以支持未来的临床发展工作。此外，我们将优化新型的MGLUS NAM，以实现选择铅临床开发候选和备份化合物所需的属性。这将需要两个主要项目的协调努力，并需要两个核心的支持。项目1将着重于动物研究，旨在进一步表征新型MGLUS NAM的行为效应和中枢神经系统占用。在项目2中，我们将基于此脚手架的新型MGLUS NAM化学优化，以达到选择可以提高辅助研究和临床开发的临床开发候选者所需的特性的平衡。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）和行政核心（核心B）。