Effective treatment of Alzheimer’s disease (AD) remains a critical unmet need in medicine. The lack of useful
treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid
β-42 (Aβ42) plays an early and crucial role in all cases of AD. β-Secretase (also known as BACE-1 β-site APP-cleaving
enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Aβ peptide
fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally,
β-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective
of the class, serious challenges with respect to blood–brain barrier (BBB) penetration and selectivity still remain.
Discovering a small molecule inhibitor of β-secretase represents an unnerving challenge but, due to its significant potential
as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this
frame, the rising availability of crystal structures of β-secretase-inhibitor complexes represents an invaluable opportunity
for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about
problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of
the early β-secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five
years, showing research progress in this field.
Keywords: Alzheimer’s disease, BACE-1, β-secretase, peptidomimetic inhibitors, protease inhibitors, small-molecule inhibitors.
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