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:
  • 金额:
    $ 72.09万
  • 依托单位:
  • 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

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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

AMY F.T. ARNSTEN其他文献

AMY F.T. ARNSTEN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('AMY F.T. ARNSTEN', 18)}}的其他基金

Prefrontal impairment with stress- NE receptor subtype mechanisms.
与压力-NE受体亚型机制有关的前额损伤。
  • 批准号:
    10655735
  • 财政年份:
    2023
  • 资助金额:
    $ 72.09万
  • 项目类别:
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
  • 批准号:
    10410566
  • 财政年份:
    2020
  • 资助金额:
    $ 72.09万
  • 项目类别:
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
  • 批准号:
    10261462
  • 财政年份:
    2020
  • 资助金额:
    $ 72.09万
  • 项目类别:
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
  • 批准号:
    10633273
  • 财政年份:
    2020
  • 资助金额:
    $ 72.09万
  • 项目类别:
Preclinical assessment of GCPII inhibitors for cognition and tau pathology
GCPII 抑制剂对认知和 tau 病理学的临床前评估
  • 批准号:
    10541131
  • 财政年份:
    2019
  • 资助金额:
    $ 72.09万
  • 项目类别:
Preclinical assessment of GCPII inhibitors for cognition and tau pathology
GCPII 抑制剂对认知和 tau 病理学的临床前评估
  • 批准号:
    10321239
  • 财政年份:
    2019
  • 资助金额:
    $ 72.09万
  • 项目类别:
Preclinical assessment of GCPII inhibitors for cognition and tau pathology
GCPII 抑制剂对认知和 tau 病理学的临床前评估
  • 批准号:
    10625706
  • 财政年份:
    2019
  • 资助金额:
    $ 72.09万
  • 项目类别:
Rapid actions of ketamine in the prefrontal cortex
氯胺酮在前额皮质中的快速作用
  • 批准号:
    9901576
  • 财政年份:
    2016
  • 资助金额:
    $ 72.09万
  • 项目类别:
mGluR2/3 influences in primate prefrontal cortex: potential for therapeutics
mGluR2/3 对灵长类前额皮质的影响:治疗潜力
  • 批准号:
    8630805
  • 财政年份:
    2014
  • 资助金额:
    $ 72.09万
  • 项目类别:
Highly evolved brain circuits in primates: molecular vulnerabilities for disease
灵长类动物高度进化的大脑回路:疾病的分子脆弱性
  • 批准号:
    8558580
  • 财政年份:
    2013
  • 资助金额:
    $ 72.09万
  • 项目类别:

相似国自然基金

靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    0 万元
  • 项目类别:
    面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
  • 批准号:
    2023JJ50274
  • 批准年份:
    2023
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
  • 批准号:
    n/a
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 批准年份:
    2019
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
  • 批准号:
    81602908
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
  • 批准号:
    81501928
  • 批准年份:
    2015
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

THE GENETICS AND FUNCTIONAL NEUROANATOMY OF AGE-ASSOCIATED MEMORY IMPAIRMENT
年龄相关记忆障碍的遗传学和功能神经解剖学
  • 批准号:
    7606738
  • 财政年份:
    2007
  • 资助金额:
    $ 72.09万
  • 项目类别:
THE GENETICS AND FUNCTIONAL NEUROANATOMY OF AGE-ASSOCIATED MEMORY IMPAIRMENT
年龄相关记忆障碍的遗传学和功能神经解剖学
  • 批准号:
    7717960
  • 财政年份:
    2007
  • 资助金额:
    $ 72.09万
  • 项目类别:
THE GENETICS AND FUNCTIONAL NEUROANATOMY OF AGE-ASSOCIATED MEMORY IMPAIRMENT
年龄相关记忆障碍的遗传学和功能神经解剖学
  • 批准号:
    7205360
  • 财政年份:
    2004
  • 资助金额:
    $ 72.09万
  • 项目类别:
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
  • 批准号:
    6305687
  • 财政年份:
    1999
  • 资助金额:
    $ 72.09万
  • 项目类别:
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
  • 批准号:
    6115572
  • 财政年份:
    1998
  • 资助金额:
    $ 72.09万
  • 项目类别:
A study on the biological features of age-associated memory impairment (AAMI).
年龄相关记忆障碍(AAMI)生物学特征的研究。
  • 批准号:
    09671003
  • 财政年份:
    1997
  • 资助金额:
    $ 72.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C).
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
  • 批准号:
    6276806
  • 财政年份:
    1997
  • 资助金额:
    $ 72.09万
  • 项目类别:
AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
  • 批准号:
    3386469
  • 财政年份:
    1990
  • 资助金额:
    $ 72.09万
  • 项目类别:
AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
  • 批准号:
    3386468
  • 财政年份:
    1990
  • 资助金额:
    $ 72.09万
  • 项目类别:
AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
  • 批准号:
    2247160
  • 财政年份:
    1990
  • 资助金额:
    $ 72.09万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了