Design of potent and highly selective inhibitors for human β-secretase 2 (memapsin 1), a target for type 2 diabetes

Design, synthesis and evaluation of very potent and selective β-secretase 2 (memapsin 1, BACE 2) inhibitors are described. The inhibitors were designed specifically to interact with the S2′-site of β-secretase 2 to provide >170 000-fold selectivity over β-secretase (BACE 1) and >15 000-fold selectivity over cathepsin D. BACE 2 is implicated in type 2 diabetes. The studies serve as an important guide to selective BACE 2 inhibitors. Structure-based design and syntheses of potent and highly selective BACE2 inhibitors are described.