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

Starting from lead compound 4, 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 pKa 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 N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic
treatment regimens.