BACE1 Inhibitors: Design, Synthesis, Structure–Activity Relationships, and Therapeutic Applications in Alzheimer’s Disease and Beyond – An Updated Review

Abstract

Beta secretase amyloid precursor protein–cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) production, making it central to therapeutic strategies for Alzheimer’s disease (AD). Since its discovery, an extraordinary amount of effort has gone into designing molecules that safely and effectively inhibit its activity. Early peptidomimetic inhibitors taught us much about how BACE1 recognizes its substrates, but their large size and poor ability to enter the brain limited their therapeutic potential. Over time, medicinal chemistry shifted toward smaller, more drug-like scaffolds—including hydroxyethylamine, aminoimidazole, aminothiazoline, aminooxazoline, hydantoin, and dihydroquinazoline frameworks—guided by structural biology, fragment-based discovery, and increasingly sophisticated computational approaches. These refinements led to potent inhibitors with greatly improved pharmacokinetic profiles. Despite these advances, clinical outcomes have been disappointing. Several of the most promising candidates, such as verubecestat, atabecestat, lanabecestat, and elenbecestat, successfully lowered Aβ levels in humans yet failed to demonstrate clinical benefit and, in some cases, raised safety concerns. These setbacks underscored a crucial point: BACE1 participates in many physiological processes beyond APP cleavage. It also regulates pathways involved in myelination, synaptic function, neuronal development, and even systemic metabolism. As a result, chronic, full inhibition may have unintended biological consequences. This review brings together the major developments in BACE1 inhibitor design, highlighting how synthetic strategies and structure–activity relationships have evolved. It also discusses emerging therapeutic opportunities outside AD and reflects on why past clinical efforts fell short. Understanding these complexities is essential for shaping the next generation of safer, more targeted BACE1-modulating therapies.