Development of mGIuR5 NAMS for Treatment of Major Depression

描述（由申请人提供）：重度抑郁症（MDD）影响了大约16%的美国人，是全球最常见的致残原因之一。不幸的是，只有不到三分之一的患者能够通过现有的药物持续缓解重度抑郁症的症状。最近的研究提出了一种令人兴奋的可能性，即代谢性谷氨酸受体mGlus亚型的高选择性拮抗剂或负变构调节剂（NAMs）可能为治疗重度抑郁症提供一种新的方法。这一机制代表了对现有疗法的根本背离，有可能提供比现有疗法更快的起效，并可能为难治性患者提供持续的缓解。在这份修订后的NCDDG申请中，我们提出了一项研究，旨在利用我们在范德比尔特神经科学药物发现中心（VCNDD）发现的新型mGlus NAMs，在动物模型中进一步验证这一机制，并进行转化研究，以支持未来的临床开发工作。此外，我们将优化新的mGlus NAMs，以获得选择主要临床开发候选药物和备用化合物所需的特性。这将需要两个主要项目的协调努力和两个核心的支持。项目1将侧重于动物研究，旨在进一步表征新型mGlus NAMs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 NAMs进行化学优化，以达到选择临床开发候选物所需的性能平衡，从而推进ind研究和临床开发。这些项目将由两个核心支持，包括生物分析和DMPK核心（核心a）和行政核心（核心B）。

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).