Hydroxyethylamine-based inhibitors of BACE1: P1aP3 macrocyclization can improve potency, selectivity, and cell activity

We describe a systematic study of how macrocyclization in the P1aP3 region of hydroxyethylamine-based inhibitors of I2-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid I2-peptide (AI2)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.