Pharmacologic Inhibition of PDE11A for Age-Related Memory Disorders

项目摘要 与年龄相关的记忆力丧失仍然是一种疾病，目前还没有有效的治疗方法。 数据表明，在大脑中与记忆相关的特定区域发现的一种酶， 随着人类年龄增长，磷酸二酯酶11A(PDE11A)的表达增加，而 大脑中作为这种酶底物的关键信号分子会相继减少， 这导致了一种假设，即PDE11A直接对这种效应负责。我们的实验 缺乏PDE11A的小鼠显示，这些动物的行为和繁殖正常，而不是 和它们的野生型后代一样，遭受着与年龄相关的记忆力丧失。此数据 共同导致假设，PDE11A可能是一个有价值的研究目标作为一种手段 来治疗与年龄相关的记忆力丧失。 目前还没有已知的有效和选择性的PDE11A抑制剂。其他一些PDE 酶正在研究或已经被研究用于各种精神病学和 神经退行性疾病，表明这个家族可以被小分子靶向。一个 利用表达人PDE11A的酵母进行新的筛选方法鉴定出许多良好的 起点。其中一些药物对PDE11A表现出极好的选择性 有潜力进行优化，以提供第一种有效的、选择性的PDE11A抑制剂 将使我们能够在与年龄相关的行为的小鼠模型中研究这些化合物，并 记忆。

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.