Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application

A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI–MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Aβ in human APP-wildtype transgenic (APP51/16) mice after oral administration.

Graphical abstractStarting from macrocyclic peptidic BACE-1 inhibitor 1, brain permeation was optimized for this series using a MDRI–MDCK assay to lead to NB-216 and analogues. These compounds show acute reduction of Aβ in brain of APP51/16 transgenic mice, after po application.Figure optionsDownload full-size imageDownload as PowerPoint slide