Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human β-secretase (BACE1)

Phosphino dipeptide (PDP) isosteres are known to be useful analogues of the transition state of metalloprotease substrates. Here we describe the use of this unit for the design of aspartic protease inhibitors. A PDP analogue of OM00-3, a potent BACE1 inhibitor, was synthesized and exhibited high biological activity (IC50 ∼ 12 nM).

Phosphino peptide 5a was synthesized and appeared as a highly active inhibitor of BACE1.Figure optionsDownload as PowerPoint slide