BACE-1 inhibitors part 2: Identification of hydroxy ethylamines (HEAs) with reduced peptidic character

This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P'(1), and P'(2) substituents, two different binding modes were observed in X-ray co-crystal structures. (C) 2007 Elsevier Ltd. All rights reserved.