Abstract: KMI-008 is a well-known lead compound in the design of potent BACE1 inhibitors, in which Pns is the core structure involved in several important interactions with BACE1. In our research for new potent BACE1 inhibitors, 4-OH or 4-NH2-substituted proline was used to study the better conformation of these two function groups. Further introduction of phenyl group by L-phenylalanine increased activity significantly. It seems that L-Phe-D-Pro could be an alternative core structure in the design of new BACE1 inhibitors. Structure-activity relationships of the BACE1 inhibitors were studied. All the peptides were synthesized by solid phase synthesis and characterized with ESI-MS.

Key words: Alzheimer’s disease, BACE1 inhibitors, peptides； proline