Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Instituto Teofilo Hernando and Departamento de Farmacología y Terapeutica, Facultad de Medicina, Universidad Autonoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain.
Eur J Med Chem. 2019 Feb 1;163:394-402. doi: 10.1016/j.ejmech.2018.12.003. Epub 2018 Dec 3.
Current healthcare has significantly increased the average life expectancy, leading to a consequently greater incidence of age-related diseases, such as Alzheimer's disease. Following a multitarget approach, in this paper a series of polycyclic maleimide-based derivatives were designed and synthesized aimed at simultaneously modulate neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), validated targets to combat Alzheimer' disease. Different structural modifications were performed on the polycyclic scaffold in order to investigate the structure-activity relationships and compound 10 emerged as a promising non-toxic lead compound, endowed with calcium modulating brain-addressed properties and significant GSK-3β inhibitory activity. Moreover, the easily affordable polycyclic core appears as a new appealing privileged structure in medicinal chemistry.
当前的医疗保健显著延长了平均寿命，导致与年龄相关的疾病（如阿尔茨海默病）的发病率相应增加。本研究采用多靶点方法，设计并合成了一系列基于多环马来酰亚胺的衍生物，旨在同时调节神经元钙通道和糖原合酶激酶 3-β（GSK-3β），这两个靶点是对抗阿尔茨海默病的有效靶点。为了研究构效关系，我们对多环支架进行了不同的结构修饰，结果化合物 10 脱颖而出，成为一种有前途的无毒先导化合物，具有调节钙的脑靶向特性和显著的 GSK-3β抑制活性。此外，这种易于获得的多环核心在药物化学中似乎是一种新的有吸引力的优势结构。
