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

开发用于治疗年龄相关认知障碍的 GCPII 抑制剂

基本信息

批准号：
10028000
负责人：
AMY F.T. ARNSTEN
金额：
$ 72.09万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10028000
关键词：
Address Age Age-associated memory impairment Aging Agonist Agreement Alzheimer&apos s disease risk Binding Brain Brain Diseases Brain region C-terminal Calcium Calcium Signaling Caring Charge Chemistry Cleaved cell Clinical Clinical Research Cognition Cognitive Cognitive deficits Computer Assisted Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Dose Drug Design Drug Kinetics Elderly Exhibits FOLH1 gene Glutamates Goals Healthcare Human Impaired cognition In Vitro Inflammation Late Onset Alzheimer Disease Lead Levodopa Maryland Mediating Medical Membrane Memory Metalloproteases Monkeys N-acetylaspartate N-acetylaspartylglutamate Neurobiology Neurons Oral Oral Administration Permeability Pharmacology Physiological Play Population Potassium Channel Prefrontal Cortex Probability Prodrugs Public Health Rattus Regimen Regulation Research Personnel Research Proposals Risk Role Signal Transduction Societies Structure Sulfhydryl Compounds Synapses Testing Therapeutic Translating Zinc age related cognitive disorder aged aging brain analog analog L association cortex clinical candidate clinical translation cognitive enhancement cognitive function cognitive testing design drug discovery efficacy study efficacy testing extracellular immunogenicity improved in vivo inhibitor/antagonist metabotropic glutamate receptors type 3 nervous system disorder novel novel strategies novel therapeutic intervention novel therapeutics positive allosteric modulator postsynaptic pre-clinical response screening side effect success tau phosphorylation translation to humans

项目摘要

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.

项目概要该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，可改善认知并降低迟发性阿尔茨海默病的风险（广告）。 GCPII (EC 3.4.17.21) 是一种膜结合锌金属肽酶，可切割 C 末端谷氨酸从 N-乙酰天冬氨酰谷氨酸 (NAAG) 产生 N-乙酰天冬氨酸和谷氨酸。 NAAG 是已知作为代谢型谷氨酸受体 3 (mGluR3) 的内源性激动剂，我们有最近发现 NAAG 可以通过刺激猴子中与记忆相关的神经元放电 Gi/Go 介导的突触后 cAMP-PKA-钙信号传导调节。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-钙信号传导失调。在缺乏 mGluR3 选择性的情况下激动剂和正变构调节剂，这种方法特别有吸引力，因为许多结构多种有效的 GCPII 抑制剂已被开发并在多种领域进行了临床前评估神经系统疾病具有强大的功效和出色的副作用。事实上，我们的初步数据在老年大鼠中使用 2-MPPA（一种经过临床测试的 GCPII 抑制剂）治疗后显示出认知能力增强和猴子。然而迄今为止，GCPII 抑制剂的临床转化工作已经取得了实质性进展。尽管具有显着的治疗潜力，但仍有限。这促使我们提出了广泛的开发脑渗透性 GCPII 抑制剂的药理学方法。我们已蓄势待发通过执行以下操作来治疗与年龄相关的认知障碍的治疗机会三个具体目标：（目标1）GCPII抑制剂及其前药的设计与合成；（目标 2）评估 GCPII 抑制剂在大鼠和猴子体内的药代动力学 (PK) 曲线；（目标 3）评估 GCPII 的效果对老年大鼠和猴子认知功能的抑制剂。该项目的成功实施将带动一种新颖的治疗策略，具有更大的临床转化可行性，以解决主要的医疗保健问题不断增长的老年人口的需求。