Structure-based design and synthesis of macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors

The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a–h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.

Graphical abstractAn X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a–h. These inhibitors show improved potency over their open-chain analogue.Figure optionsDownload full-size imageDownload as PowerPoint slide