Progress toward the development of a viable BACE‐1 inhibitor

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive formation of insoluble amyloid plaque and fibrillary tangles. Plaques are extracellular constructs consisting primarily of Aβ42 derived from the catabolism of β‐amyloid precursor protein (APP). β‐Secretase (BACE‐1) is the enzyme responsible for the initiatory cleavage event in APP catabolism. The central role of BACE‐1 in the production of Aβ42 has made it an attractive target for drug development. However, the development of BACE‐1 inhibitors has been hampered by difficulty in identifying inhibitors with acceptable pharmacokinetic and CNS penetration properties. The maturation of the BACE‐1 drug discovery effort from typical peptidomimetic inhibitors to more novel structural classes is reviewed. Drug Dev Res 70, 2009.