3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3尾 Fragment Hits against Alzheimer鈥檚 Disease
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- 作者：Federica Prati ; Angela De Simone ; Andrea Armirotti ; Maria Summa ; Daniela Pizzirani ; Rita Scarpelli ; Sine Mandrup Bertozzi ; Daniel I. Perez ; Vincenza Andrisano ; Ana Perez-Castillo ; Barbara Monti ; Francesca Massenzio ; Letizia Polito ; Marco Racchi ; Piera Sabatino ; Giovanni Bottegoni ; Ana Martinez ; Andrea Cavalli ; Maria L. Bolognesi
- 刊名：ACS Chemical Neuroscience
- 出版年：2015
- 出版时间：October 21, 2015
- 年：2015
- 卷：6
- 期：10
- 页码：1665-1682
- 全文大小：811K
- ISSN：1948-7193
文摘
One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3尾 dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 渭M against BACE-1 and GSK-3尾, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimer鈥檚 disease models.