Development of GCPII inhibitors for the treatment of age-related cognitive disorders

项目摘要 本研究计划的目标是开发谷氨酸羧肽酶II的脑渗透抑制剂 （GCPII）作为一种新的治疗策略，以改善认知和降低迟发性阿尔茨海默病的风险 （AD）。GCPII（EC 3.4.17.21）是一种膜结合的锌金属肽酶，其切割C-末端 从N-乙酰基天冬氨酸谷氨酸盐（NAAG）产生N-乙酰基天冬氨酸盐和谷氨酸盐。NAAG是 已知作为代谢型谷氨酸受体3型（mGluR 3）的内源性激动剂， 最近发现，NAAG可以通过刺激神经元增强猴子的记忆相关神经元放电。 Gi/Go介导的突触后cAMP-PKA-钙信号转导的调节。因此，GCPII抑制可能 通过增加细胞外NAAG水平为认知障碍提供新的治疗方法， 控制衰老大脑中cAMP-PKA-钙信号失调。在不存在mGluR 3选择性的情况下， 激动剂和正变构调节剂，这种方法是特别有吸引力的，因为许多结构上 已经开发了多种有效的GCPII抑制剂，并在多种临床试验中进行了临床前评价。 神经系统疾病，具有强大的功效和优异的副作用特征。事实上，我们的初步数据 在老年大鼠中用2-MPPA（一种临床测试的GCPII抑制剂）治疗后显示认知增强 还有猴子然而，迄今为止，对GCPII抑制剂的临床转化的努力已经实质上是失败的。 尽管具有显著的治疗潜力，但仍然有限。这促使我们提出了一系列广泛的 开发脑渗透性GCPII抑制剂的药理学方法。我们准备抓住 通过执行以下步骤来治疗年龄相关认知障碍的治疗机会 三个具体目的：（目的1）GCPII抑制剂及其前药的设计和合成;（目的2）评价 GCPII抑制剂在大鼠和猴中的药代动力学（PK）特征;（目的3）评估GCPII抑制剂的作用 抑制剂对老年大鼠和猴子认知功能的影响。该项目的成功实施将导致 一种新的治疗策略，具有更大的临床转化可行性，以解决主要的医疗保健问题， 满足日益增长的老年人口的需求。

Project Summary The goal of this research proposal is to develop brain-penetrant inhibitors of glutamate carboxypeptidase II (GCPII) as a new therapeutic strategy to improve cognition and reduce risk of late-onset Alzheimer's Disease (AD). GCPII (EC 3.4.17.21) is a membrane-bound zinc metallopeptidase that cleaves the C-terminal glutamate from N-acetylaspartylglutamate (NAAG) producing N-acetylaspartate and glutamate. NAAG is known to act as an endogenous agonist at metabotropic glutamate receptor type 3 (mGluR3) and we have recently found that NAAG can enhance memory-related neuronal firing in monkeys through stimulation of Gi/Go-mediated regulation of postsynaptic cAMP-PKA-calcium signaling. Therefore, GCPII inhibition may offer a new therapeutic approach to the cognitive impairments by increasing extracellular NAAG levels and controlling cAMP-PKA-calcium signaling dysregulated in the aging brain. In the absence of mGluR3-selective agonists and positive allosteric modulators, this approach is particularly attractive as a number of structurally diverse and potent GCPII inhibitors have been developed and preclinically evaluated in a variety of neurological disorders with a robust efficacy and an excellent side effect profile. Indeed, our preliminary data show cognitive enhancement upon treatment with 2-MPPA, a clinically tested GCPII inhibitor, in aged rats and monkeys. To date, however, efforts on clinical translation of GCPII inhibitors have been substantially limited despite the significant therapeutic potential. This prompted us to propose a broad range of pharmacological approaches to the development of brain-penetrant GCPII inhibitors. We are poised to seize this therapeutic opportunity for the treatment of age-related cognitive disorders by executing the following three Specific Aims: (Aim 1) Design and synthesis of GCPII inhibitors and their prodrugs; (Aim 2) Evaluate the pharmacokinetic (PK) profile of GCPII inhibitors in rats and monkeys; (Aim 3) Assess the effects GCPII inhibitors on cognitive function in aged rats and monkeys. The successful execution of this project will lead to a novel therapeutic strategy with greater feasibility for clinical translation to address the main healthcare needs of the growing elderly population.