First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.
First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.
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DOI：
10.1021/acs.jmedchem.3c01088
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发表时间：
2023-11-09
影响因子：
7.3
通讯作者：
Rotella, David
中科院分区：
文献类型：
--
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
磷酸二酯酶11A4 （PDE11A4）是一种双作用环核苷酸水解酶，表达于海马延伸形成的CA1、下丘、杏仁核纹状体过渡区和杏仁核海马区神经元中。PDE11A4是唯一一种仅从海马体生成的PDE酶，海马体是形成长期记忆的关键大脑区域。PDE11A4的表达在人类和啮齿动物的海马形成中随着年龄的增长而增加。有趣的是，PDE11A基因敲除小鼠没有表现出与年龄相关的联想记忆缺陷，也没有表现出大体的组织病理学。这表明抑制PDE11A4可能是治疗与年龄相关的认知衰退的一种选择。一种新的、基于酵母的高通量筛选方法先前鉴定出了中等效力的、选择性的PDE11A4抑制剂，这项工作描述了将这些支架中的一种的效力提高10倍以上，并改善了一些药物特性，从而产生了选择性的、细胞渗透的PDE11A4抑制剂，其中一种的细胞活性比他达拉非强10倍。
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.
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影响因子：
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作者：
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