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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.

项目总结