Design of Substrate-Based Inhibitors of Human β-Secretase

By use of the effectively cleaved β-secretase (BACE) substrate (1), incorporation of a statine in P1 resulted in a weak inhibitor 13 of the enzyme. Further substitution of P1‘-Asp by P1‘-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P10−P5 residues on the N-terminal part of inhibitor 22 resulted in no loss of potency (23). C-terminal truncations of inhibitor 22 generally led to significant loss of potency.