Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.

Graphical abstractThis article discloses the strategy that led to stable hydroxyethylamine BACE-1 inhibitors with nanomolar cell potency and good oral bioavailability and give insights into the design of compounds with the potential of increased brain penetration.Figure optionsDownload full-size imageDownload as PowerPoint slide