3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3 beta Fragment Hits against Alzheimer's Disease

作者：Prati Federica; De Simone Angela; Armirotti Andrea; Surnma Maria; Pizzirani Daniela; Scarpelli Rita; Bertozzi Sine Mandrup; Perez Daniel I; Andrisano Vincenza; Perez Castillo Ana; Monti Barbara; Massenzio Francesca; Polito Letizia; Racchi Marco; Sabatino Piera; Bottegoni Giovanni; Martinez Ana; Cavalli Andrea^*; Bolognesi Maria L

来源：ACS Chemical Neuroscience, 2015, 6(10): 1665-1682.

DOI：10.1021/acschemneuro.5b00121

• Alzheimer's disease
• 6-amino-3,4-dihydro-1,3,5-triazin-2(1H)-one
• drug design
• multitarget-directed ligands
• multitarget drug discovery
• beta-secretase
• glycogen-synthase kinase-3 beta

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 beta 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 mu M against BACE-1 and GSK-3 beta, 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's disease models.

• 出版日期2015-10