The Design, Development, and Evaluation of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a very serious public health problem. Currently, there is no effective treatment for AD. Among the many biochemical targets for AD drug development, β-secretase (BACE1, memapsin 2) continues to be a promising drug discovery target for AD therapy. This proteolytic enzyme is a membrane-anchored aspartic acid protease that is responsible for the initial step of amyloid precursor protein (APP) cleavage, leading to the production of neurotoxic amyloid-β (Aβ) peptides in the brain. Since its identification and structural elucidation in 1999, extensive research efforts have led to the development of many promising classes of inhibitors against this protease. Structure-based design strategies led to the evolution of many small-molecule, peptidomimetic, and nonpeptide BACE1 inhibitors that have now overcome the key development challenges including selectivity and brain penetration. To date, 13 BACE1 drug candidates have been brought to clinical trials, and a number of them have advanced to phase II/III human trials. This chapter illustrates structure-based evolution of various classes of BACE inhibitors. Also, it provides a perspective on BACE1 inhibitor drugs for the treatment of AD patients.