Pharmacologic Inhibition of PDE11A for Age-Related Memory Disorders

PDE11A 对年龄相关记忆障碍的药理学抑制作用

基本信息

批准号：
10617261
负责人：
CHARLES S. HOFFMAN
金额：
$ 72.6万
依托单位：
MONTCLAIR STATE 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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617261
关键词：
Acute Address Adverse event Age Age-Related Memory Disorders Age-associated memory impairment Aging Animal Model Animals Anterior Anxiety Area Attention Behavior Behavioral Biological Assay Biological Availability Brain Brain region Cells Controlled Study Cyclic AMP Cyclic GMP Data Dementia Disease Disease model Dose Drug Kinetics Drug Targeting Enzymes Evaluation Family Genes Genetic Health Hippocampal Formation Hippocampus Human Impaired cognition In Vitro Investigation Knock-out Lead Libraries Literature Mammalian Cell Measures Mediating Memory Memory Loss Memory impairment Mental Depression Mental disorders Methods Motor Motor Activity Mus Mutant Strains Mice Neurodegenerative Disorders Neurons Oral Performance Permeability Phosphorylation Physiological Primates Protein Isoforms Proteins Research Rodent Sensory Signal Transduction Signaling Molecule Social Behavior Social Interaction System Viral Yeasts age related aged analog behavioral study candidate validation cohort demented effective therapy enzyme substrate experimental study improved in vivo in vivo Model inhibitor innovation long term memory memory retrieval mouse model novel novel therapeutic intervention pharmacologic phosphodiesterase 11a prevent screening side effect small molecule small molecule inhibitor therapeutic target

项目摘要

Project Summary Age-related loss of memory remains a disease for which there are no effective treatments. Data suggests that an enzyme found in a specific region of the brain associated with memory, phosphodiesterase 11A (PDE11A), is increasingly expressed as humans age, and that levels of key signaling molecules in the brain that are substrates for this enzyme decrease in tandem, leading to the hypothesis that PDE11A is directly responsible for this effect. Our experiments with mice lacking PDE11A revealed that these animals behave and reproduce normally and do not suffer from the same age related loss of memory as their wild type littermates. This data collectively leads to the hypothesis that PDE11A may be a valuable target for study as a means to treat age-related loss of memory. There are no known potent and selective PDE11A inhibitors. A number of other PDE enzymes are under investigation or have been studied for various psychiatric and neurodegenerative diseases, indicating that this family can be targeted by small molecules. A novel screening method using yeast that express human PDE11A identified a number of good starting points. Some of these hits demonstrated excellent selectivity for PDE11A with the potential to be optimized to provide the first potent, selective PDE11A inhibitors with a profile that will allow us to investigate these compounds in mouse models of age-related behavior and memory.

项目摘要与年龄相关的记忆丧失仍然是一种没有有效治疗的疾病。数据表明，在与记忆相关的大脑特定区域中发现的酶，磷酸二酯酶11A（PDE11A）越来越表达为人类的年龄大脑中的关键信号分子是这种酶的底物，串联降低，导致假设PDE11a直接负责这种效果。我们的实验缺乏PDE11A的小鼠表明，这些动物的行为正常并繁殖与年龄相关的记忆丧失与野生型同窝脚同同级。这个数据总体导致以下假设，即PDE11A可能是学习的宝贵目标治疗与年龄相关的记忆丧失。没有已知的有效和选择性PDE11A抑制剂。其他一些PDE 酶正在研究或已研究各种精神科和神经退行性疾病，表明该家族可以由小分子靶向。一个使用表达人PDE11A的酵母的新型筛查方法确定了许多好的起点。这些热门单曲中的一些对PDE11a表现出极好的选择性优化的潜力以提供第一个有效的选择性PDE11A抑制剂，并具有一个特征将使我们能够在与年龄相关行为的鼠标模型中调查这些化合物记忆。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.

DOI：
10.1021/acs.jmedchem.3c01088
发表时间：
2023-11-09
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Mahmood, Shams ul;Lozano Gonzalez, Mariana;Tummalapalli, Sreedhar;Eberhard, Jeremy;Ly, Judy;Hoffman, Charles;Kelly, Michy;Gordon, John;Colussi, Dennis;Childers, Wayne;Rotella, David
通讯作者：
Rotella, David