Macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors with activity in vivo

The macrocyclic peptidic BACE-1 inhibitors 2a–c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P′ moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.

Graphical abstractThe macrocyclic peptidic BACE-1 inhibitors 2a–c were optimized to the highly potent and selective inhibitor 3. This compound shows inhibition of BACE-1 in the brain of APP51/16 transgenic mice, after intravenous application.Figure optionsDownload full-size imageDownload as PowerPoint slide