Lead optimization of Novel mGlu2 Negative Allosteric Modulators

新型 mGlu2 负变构调节剂的先导化合物优化

• 批准号: 9029750
• 负责人: Nicholas David Cosford
• 金额: $ 89.62万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029750
• 关键词: AMPA Receptors; Acids; Address; Adverse event; Affect; Agitation; Allosteric Site; Anhedonia; Antidepressive Agents; Back; Biological Assay; Cause of Death; Cell Proliferation; Characteristics; Chemicals; Chemistry; Data; Development; Dimensions; Disease; Drug Kinetics; Emotions; Etiology; Excretory function; FRAP1 gene; Foundations; Glutamates; Health Care Costs; Hippocampus (Brain); Human; In Vitro; Income; Interdisciplinary Study; Ketamine; Laboratories; Lead; Major Depressive Disorder; Mediating; Medical; Metabolism; Metabotropic Glutamate Receptors; N-Methyl-D-Aspartate Receptors; National Institute of Mental Health; Neurobiology; Neurons; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Prevalence; Productivity; Property; Prosencephalon; Recurrence; Reporting; Research Domain Criteria; Resistance; Rewards; Rodent; Rodent Model; Role; Selective Serotonin Reuptake Inhibitor; Series; Sexual Dysfunction; Sirolimus; Site; Suicide; Swimming; Symptoms; System; Tail Suspension; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Treatment outcome; absorption; behavioral study; compliance behavior; cost; depressive symptoms; design; drug discovery; gastrointestinal symptom; high risk; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; innovation; nervous system disorder; neural circuit; neuropsychiatric disorder; neuropsychiatry; novel; preclinical study; programs; public health relevance; receptor; research study; response; reward processing; small molecule; tool; transmission process; treatment response; treatment-resistant depression

 DESCRIPTION (provided by applicant): This R01 application entitled "Lead Optimization of Novel mGlu2 Negative Allosteric Modulators" is in response to PAR-13-048 "Drug Discovery for Nervous System Disorders". Major depressive disorder (MDD) is a serious disorder with an estimated lifetime prevalence of 19% and a societal cost >$83 billion a year in the USA. As with many other neuropsychiatric disorders, MDD is characterized by debilitating deficits in reward processing and dysfunctional neural circuitries mediating reward. Unfortunately, ~30-50% of patients suffer from treatment resistant depression (TRD) and do not respond to currently available antidepressants. Hence, there is a critical unmet need to develop effective therapeutics. Accumulating evidence suggests that the glutamatergic system may play an important role in the etiology, neurobiology, and potential management of reward processing deficits (RPDs). For example, group II metabotropic glutamate receptor (mGlu2 and mGlu3) antagonists have rapid and long-lasting antidepressant-like effects in multiple rodent tests of antidepressant activity. Antagonism of mGlu2/3 also increases neuronal proliferation in the hippocampus, an effect hypothesized to mediate antidepressant activity. However, it remains unclear whether group II mGlu antagonists may be effective for the management of RPDs that are resistant to current antidepressant medications. In the last decade, we have focused on developing small molecule group II mGlu allosteric modulators, which interact at less conserved allosteric sites topographically distinct from the mGlu orthosteric (glutamate) site. We have developed both lead and back-up series of mGlu2 negative allosteric modulators (NAMs) that are ready for full-scale chemistry optimization to provide compounds for suitable for behavioral studies. Thus, the overall objective of this project is to develop orally active mGlu2 NAMs for advanced in vivo proof-of-concept studies for the treatment of RPDs. Our Specific Aims are: 1) Design and synthesize optimized mGlu2 NAMs that are orally active in vivo; 2) Assess the potency and selectivity of mGlu2 NAMs in relevant in vitro assays; 3) Evaluate novel small molecule mGlu2 NAMs using in vitro ADME/T and in vivo pharmacokinetic (PK) assays; and 4) Characterize lead mGlu2 NAM probes in rodent in vivo models of antidepressant activity, anhedonia, and reward responsiveness. The mGlu2-selective NAMs generated will provide powerful tools for testing the role of mGlu2 in vivo. We are uniquely positioned to develop potent and selective small molecule mGlu2 NAMs with excellent PK properties for in vivo proof-of-concept studies, prior to the initiation of IND enabling studies. This multidisciplinary research program has the potential for significant scientific and medical impact by contributing to the discovery of new medications for neuropsychiatric disorders characterized by RPDs.

 描述（应用程序提供）：此R01应用名为“新型MGLU2负相变形调节剂的铅优化”是对PAR-13-048“神经系统疾病的药物发现”的响应。重度抑郁症（MDD）是一种严重的疾病，估计终生患病率为19％，社会成本>每年> 830亿美元。与许多其他神经精神疾病一样，MDD的特征是使奖励处理和功能障碍的神经信条介导了奖励。不幸的是，约有30％至50％的患者患有耐药性抑郁症（TRD），并且对当前可用的抗抑郁药反应不反应。因此，开发有效疗法的至关重要的需要。积累的证据表明，谷氨酸能系统可能在病因，神经生物学和奖励处理缺陷（RPDS）的潜在管理中起重要作用。例如，在多种抗抑郁活性的啮齿动物测试中，II组代谢型谷氨酸受体（MGLU2和MGLU3）具有快速和持久的抗抑郁样作用。 MGLU2/3的拮抗作用还增加了海马中的神经元增殖，这是中位抗抑郁活性的效应。但是，目前尚不清楚II组MGLU拮抗剂是否可能有效地管理对当前抗抑郁药的耐药性RPD。在过去的十年中，我们专注于开发小分子II MGLU变构调节剂，这些调节剂在较少组成的变构位点相互作用在地形上与MGLU矫形器（谷氨酸）位点不同。我们已经开发了铅和备份系列MGLU2负变构调节剂（NAM），它们准备进行全尺度化学优化，以提供适合行为研究的化合物。这是该项目的总体目标是开发口服活性的MGLU2 NAM，用于用于治疗RPD的体内概念验证研究。我们的具体目的是：1）设计和合成在体内口服活性的优化MGLU2 NAM； 2）评估相关体外测定中MGLU2 NAM的效力和选择性； 3）使用体外ADME/T和体内药代动力学（PK）分析评估新型的小分子MGLU2 NAM； 4）表征铅MGLU2 NAM问题在抗抑郁活性，Anhedonia和奖励反应性的体内模型中的啮齿动物中问题。 MGLU2选择性的NAMS生成的NAM将为测试MGLU2在体内的作用提供强大的工具。在建立IND促进研究的倡议之前，我们的独特位置可以在具有出色的体内概念验证研究的pK特性中开发潜在的和选择性的小分子MGLU2 NAM。该多学科研究计划有助于发现以RPD为特征的神经精神疾病的新药物，从而产生重大科学和医学影响。