BACE-1 inhibitors part 3: Identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells

Modifications to the non-prime side of a series of BACE-1 inhibitors are presented. This final round of optimisation led to inhibitors with nanomolar potency in a cell-based assay which were capable of lowering amyloid production in an animal model following oral administration. This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.