Design of Substrate-Based Inhibitors of Human β-Secretase

By use of the effectively cleaved <i>β</i>-secretase (BACE) substrate (<b>1</b>), incorporation of a statine in P<sub>1</sub> resulted in a weak inhibitor <b>13 </b>of the enzyme. Further substitution of P<sub>1</sub>‘-Asp by P<sub>1</sub>‘-Val in <b>13</b> results in a potent inhibitor <b>22</b> of BACE. Removal of the P<sub>10</sub>−P<sub>5</sub> residues on the N-terminal part of inhibitor <b>22</b> resulted in no loss of potency (<b>23</b>). C-terminal truncations of inhibitor <b>22</b> generally led to significant loss of potency.