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

项目摘要 这项研究计划的目标是开发谷氨酸羧肽酶II的脑穿透性抑制剂。 (GCPII)作为改善认知和降低晚发性阿尔茨海默病风险的新治疗策略 (Ad)。GCPII(EC 3.4.17.21)是一种膜结合的锌金属肽酶，裂解C-末端 从N-乙酰天冬氨酸(NAAG)生成N-乙酰天冬氨酸和谷氨酸的谷氨酸。NAAG是 已知在代谢性谷氨酸受体3型(MGluR3)中起内源性激动剂的作用，我们有 新近发现NAAG可通过刺激下丘脑室旁核增强猴记忆相关神经元的放电。 GI/GO介导的突触后cAMP-PKA-钙信号的调节因此，抑制GCPII可能 通过提高细胞外NAAG水平，为认知障碍的治疗提供新的途径 控制cAMP-PKA-钙信号在衰老脑中的失调。在缺少选择性mGluR3的情况下 激动剂和正变构调节剂，这种方法特别吸引人，因为许多结构 各种有效的GCPII抑制剂已经被开发出来，并在临床前评估了各种 具有强大疗效和极佳副作用的神经性疾病。事实上，我们的初步数据 经临床测试的GCPII抑制剂2-MPPA对老年大鼠的认知增强作用 还有猴子。然而，到目前为止，GCPII抑制剂的临床翻译工作基本上是 尽管有巨大的治疗潜力，但仍是有限的。这促使我们提出了广泛的 开发脑穿透性GCPII抑制剂的药理学方法。我们已经准备好抓住 这是治疗年龄相关认知障碍的治疗机会，通过执行以下步骤 三个具体目标：(目标1)设计和合成GCPII抑制剂及其前药；(目标2)评价 GCPII抑制剂在大鼠和猴体内的药代动力学(PK)；(目标3)评价GCPII的作用 对老龄大鼠和猴认知功能的抑制作用。这一项目的成功实施将导致 一种新的治疗策略，具有更大的临床翻译可行性，以解决主要的医疗保健问题 不断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.