Department of Chemistry & Biochemistry, Montclair State University, Montclair, New Jersey 07043, United States.
Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
J Med Chem. 2023 Nov 9;66(21):14597-14608. doi: 10.1021/acs.jmedchem.3c01088. Epub 2023 Oct 20.
Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.
磷酸二酯酶 11A4（PDE11A4）是一种双功能环核苷酸水解酶，在 CA1、下托、杏仁核纹状体过渡区和扩展海马结构的杏仁海马区的神经元中表达。PDE11A4 是唯一一种仅从海马结构中产生的 PDE 酶，海马结构是形成长期记忆的关键脑区。随着年龄的增长，人类和啮齿动物的海马结构中 PDE11A4 的表达增加。有趣的是，PDE11A 敲除小鼠在联想记忆方面没有表现出与年龄相关的缺陷，也没有明显的大体组织病理学改变。这表明抑制 PDE11A4 可能是治疗与年龄相关的认知能力下降的一种选择。先前的一项基于酵母的高通量筛选发现了中等效力、选择性 PDE11A4 抑制剂，本研究描述了最初的努力，这些努力使效力提高了 10 多倍，并改善了其中一种支架的一些药物特性，从而产生了选择性、细胞穿透性 PDE11A4 抑制剂，其中一种在基于细胞的活性方面比他达拉非强 10 倍。
