Trisubstituted of 1,3,5-Triazines and their Effect on BACE1

Alzheimer's disease (AD) is a multifactorial neurological disease of unknown etiology that is associated with various risk factors. Various pharmacological approaches targeting distinct mechanisms have been investigated; however, they have not yet achieved disease-modifying effects. A series of nine trisubstituted 1,3,5-triazine-based derivatives was investigated as potential inhibitors of the β-secretase enzyme (beta-site amyloid precursor protein-cleaving enzyme 1, BACE1), one of the key enzymes in the pathogenesis of AD. Although triazine-based derivatives were recognized as BACE1 inhibitors, at a concentration of 10 µM the compounds demonstrated completely insignificant activity, only methyl (4-{4-[(2,3-dihydroxypropyl)amino]-6-[(4-sulfamoylbenzyl)amino]-1,3,5-triazin-2-yl}piperazin-1-yl)acetate and 4-({4-chloro-6-[(3-hydroxypropyl)amino]-1,3,5-triazin-2-yl}amino)benzenesulfonamide showed approximately 9% and 2% inhibition of BACE1 activity, respectively.