Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors

A new series of bis-statine based peptidomimetic inhibitors of human β-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate–enzyme interaction are disclosed herein.