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（由申请人提供）：这个题为“新型 mGlu2 负变构调节剂的先导优化”的 R01 申请是对 PAR-13-048“神经系统疾病的药物发现”的回应，重度抑郁症 (MDD) 是一种严重的疾病。在美国，估计终生患病率为 19%，每年造成的社会损失超过 830 亿美元。 MDD 的特点是奖赏处理功能障碍和介导奖赏的神经回路功能障碍，不幸的是，约 30-50% 的患者患有治疗抵抗性抑郁症 (TRD)，并且对目前可用的抗抑郁药物没有反应，因此存在严重的未满足需求。越来越多的证据表明，谷氨酸能系统可能在病因学、神经生物学和奖励处理缺陷（RPD）的潜在管理中发挥重要作用。代谢型谷氨酸受体（mGlu2 和 mGlu3）拮抗剂在多项啮齿类动物的抗抑郁活性测试中具有快速且持久的抗抑郁样作用，mGlu2/3 的拮抗作用也会增加海马的神经元增殖，而这种作用会被破坏以介导抗抑郁活性。目前尚不清楚 II 类 mGlu 拮抗剂是否可以有效治疗对当前抗抑郁药物耐药的 RPD。在过去的十年中，我们专注于开发小分子 II 类 mGlu 变构调节剂，它们在与 mGlu 正构（谷氨酸）位点不同的不太保守的变构位点上相互作用。我们开发了领先和备用系列的 mGlu2 负变构调节剂。 （NAM）已准备好进行全面化学优化，以提供适合行为研究的化合物因此，该项目的总体目标是开发口服活性 mGlu2。用于治疗 RPD 的先进体内概念验证研究的具体目标是：1) 设计和合成体内具有口服活性的优化 mGlu2 NAM；2) 评估 mGlu2 NAM 在相关领域的效力和选择性。 3) 使用体外 ADME/T 和体内药代动力学 (PK) 测定评估新型小分子 mGlu2 NAM；4)表征啮齿类动物体内抗抑郁活性、快感缺乏和奖赏反应模型中的先导 mGlu2 NAM 探针。生成的 mGlu2 选择性 NAM 将为测试 mGlu2 体内作用提供强大的工具。在启动 IND 启动研究之前，mGlu2 NAM 具有出色的 PK 特性，可用于体内概念验证研究。通过帮助发现以 RPD 为特征的神经精神疾病的新药物，产生了重大的科学和医学影响。