Lead optimization of Novel mGlu2 Negative Allosteric Modulators

 描述（由申请人提供）：本R 01申请题为“新型mGlu 2负变构调节剂的先导优化”，是对PAR-13-048“神经系统疾病药物发现”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%，每年的社会成本> 830亿美元。与许多其他神经精神疾病一样，MDD的特征是奖励处理中的衰弱缺陷和介导奖励的神经回路功能障碍。不幸的是，约30-50%的患者患有难治性抑郁症（TRD），并且对目前可用的抗抑郁药没有反应。因此，存在开发有效治疗剂的关键未满足的需求。越来越多的证据表明，脑电能系统可能在奖赏加工缺陷（RPDs）的病因学、神经生物学和潜在管理中发挥重要作用。例如，II组代谢型谷氨酸受体（mGlu 2和mGlu 3）拮抗剂在抗抑郁活性的多种啮齿动物试验中具有快速和持久的抗抑郁样作用。mGlu 2/3的拮抗作用还增加海马中的神经元增殖，这是一种假设介导抗抑郁活性的效应。然而，目前尚不清楚II组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，我们一直专注于开发小分子II组mGlu变构调节剂，其在与mGlu正构（谷氨酸）位点在地形上不同的不太保守的变构位点相互作用。我们已经开发了mGlu 2负变构调节剂（NAM）的先导和备用系列，这些系列已准备好进行全面的化学优化，以提供适合行为研究的化合物。因此，本项目的总体目标是开发口服活性mGlu 2 NAM，用于治疗RPD的先进体内概念验证研究。我们的具体目标是：1）设计和合成在体内具有口服活性的优化的mGlu 2 NAM; 2）在相关的体外测定中评估mGlu 2 NAM的效力和选择性; 3）使用体外ADME/T和体内药代动力学（PK）测定来评估新型小分子mGlu 2 NAM;以及4）在抗抑郁活性、快感缺乏和奖赏响应性的啮齿动物体内模型中表征前导mGlu 2 NAM探针。产生的mGlu 2选择性NAM将为测试mGlu 2在体内的作用提供有力的工具。在IND启动研究之前，我们具有独特的优势，可以开发具有优异PK特性的强效和选择性小分子mGlu 2 NAM，用于体内概念验证研究。这个多学科的研究项目有可能通过发现以RPD为特征的神经精神疾病的新药物来产生重大的科学和医学影响。

 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.