TY - JOUR
T1 - BACE-1 Inhibitors
T2 - From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease
AU - Prati, Federica
AU - Bottegoni, Giovanni
AU - Bolognesi, Maria Laura
AU - Cavalli, Andrea
N1 - We thank the University of Bologna and the Italian Institute of Technology for financial support.
PY - 2018/2/8
Y1 - 2018/2/8
N2 - The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.
AB - The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.
U2 - 10.1021/acs.jmedchem.7b00393
DO - 10.1021/acs.jmedchem.7b00393
M3 - Review article
C2 - 28749667
AN - SCOPUS:85041804152
SN - 0022-2623
VL - 61
SP - 619
EP - 637
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -