Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360

Abstract

Starting from lead compound <b>4</b>, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF₃ group delivered an excellent pharmacological profile with a p<i>K</i>_a of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent <i>N</i>-(3-((3<i>R</i>,6<i>R</i>)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2<i>H</i>-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide <b>54</b> (<b>NB-360</b>), able to reduce significantly A<i>β</i> levels in mice, rats, and dogs in acute and chronic treatment regimens.