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Discovery of PDE2A inhibitors to treat memory deficits in mild cognitive impairment and Alzheimer's disease

发现 PDE2A 抑制剂可治疗轻度认知障碍和阿尔茨海默氏病的记忆缺陷

基本信息

批准号：
10255641
负责人：
Fu Du
金额：
$ 49.98万
依托单位：
FD NEUROTECHNOLOGIES CONSULTING & SERVICES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255641
关键词：
Acetylcholine Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient American Amygdaloid structure Animal Model Arizona Behavioral Biological Assay Biological Availability Brain Brain region Brain-Derived Neurotrophic Factor Buffaloes CREB1 gene Cell Culture Techniques Cell model Cells Characteristics Chemicals Clinical Clinical Research Clinical Trials Cognition Disorders Cognitive Cognitive deficits Collaborations Cyclic AMP Cyclic GMP Data Dementia Dendrites Development Disease Disease Progression Drug Kinetics Early treatment Enzymes Evaluation Glutamates Goals Half-Life Hippocampus (Brain)Impaired cognition In Vitro Inflammatory Investigation Laboratories Lead Length Link Memory Memory impairment Metabolic Metabolism Modeling Mood Disorders Mus Mutation Neurons Oral PDE2 phosphodiesterase Patients Penetrance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Plasma Prefrontal Cortex Property Purines Research Senile Plaques Signal Transduction Small Business Innovation Research Grant Structure Structure of area postrema Structure-Activity Relationship TNF gene Techniques Testing Therapeutic Agents Time Universities Vomiting analog base clinical candidate clinical development common symptom cytokine design drug candidate drug discovery druggable target gastrointestinal in silico in vivo inhibitor/antagonist lead candidate lead optimization mild cognitive impairment morris water maze mouse model neuroinflammation neurotechnology new therapeutic target novel novel therapeutics object recognition phosphoric diester hydrolase pre-clinical preclinical development prevent programs safety study side effect spatial memory therapy development tool

项目摘要

Abstract Despite the fact that more than 50% of early stage of Alzheimer’s disease (AD) patients with mild cognitive impairment (MCI) will progress to dementia within 5 years, current therapies provide minimal symptomatic relief, without curing or halting disease progression. Phosphodiesterase-2A (PDE2A), the most prevalent of PDEs expressed in the cortex, hippocampus and amygdala, regions involved in cognitive impairment, has emerged as a promising target for the treatment of mild cognitive impairment without side effects. Despite promising preclinical data showing that some inhibitors of PDE2A inhibitors, such as Bay 60-7550 and ND 7001, enhance memory in animal models of AD, clinical studies have not advanced, due in part, to the low selectivity, poor metabolic stability and brain penetrance of available compounds. The broad, long-term goal of this project is to discover and develop novel inhibitors of PDE2A for the treatment of MCI. To streamline the exciting project toward a clinical candidate, we have assembled a team with expertise in medicinal chemistry and drug discovery and PDE-related pharmacology and pharmacokinetics. The complementary collaboration among FD Neurotechnologies (Dr. Fu Du), University at Buffalo (Drs. Ying Xu and James M. O’Donnell), and University of Arizona (Dr. Wei Wang) will synergize the effort by utilizing state-of-the-art drug discovery tools and techniques to discover and optimize novel and drug-like inhibitors of PDE2A and to evaluate their pharmacological effects in cell and animal models.

摘要尽管事实上，超过50%的早期阿尔茨海默病（AD）患者有轻度认知障碍，轻度认知功能障碍（MCI）将在5年内进展为痴呆，目前的治疗提供了最小的症状缓解，而不治愈或阻止疾病进展。磷酸二酯酶-2A（PDE 2A），最普遍的 PDE在皮质、海马和杏仁核中表达，这些区域与认知障碍有关，成为治疗轻度认知障碍而无副作用的有希望的靶点。尽管有希望的临床前数据显示，PDE 2A抑制剂的一些抑制剂，如Bay 60-7550和ND 7001，增强记忆在AD动物模型中，临床研究尚未取得进展，部分原因是，选择性差、代谢稳定性差和脑转移性差。广泛的，长期的目标本项目旨在发现和开发新型PDE 2A抑制剂，用于治疗MCI。精简一个令人兴奋的临床候选人项目，我们组建了一个具有药物化学专业知识的团队以及药物发现和PDE相关的药理学和药代动力学。互补合作在FD Neurotechnologies（Fu Du博士）、布法罗大学（Ying Xu博士和James M.奥唐纳），以及亚利桑那大学（王伟博士）将通过利用最先进的药物发现工具来协同努力和技术，以发现和优化新型和药物样的PDE 2A抑制剂，并评估其细胞和动物模型中的药理作用。