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Home > BACE1 Inhibitors for Alzheimer's Disease: Current Challenges and Future Perspectives.

TitleBACE1 Inhibitors for Alzheimer's Disease: Current Challenges and Future Perspectives.
Publication TypeJournal Article
Year of Publication2024
AuthorsCoimbra, JRM, Resende, R, Custódio, JBA, Salvador, JAR, Santos, AE
JournalJ Alzheimers Dis
Volume101
Issues1
PaginationS53-S78
Date Published2024
ISSN1875-8908
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Enzyme Inhibitors, Humans
Abstract

Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.

DOI10.3233/JAD-240146
Alternate JournalJ Alzheimers Dis
PubMed ID38943390
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Source URL: https://www.j-alz.com/content/bace1-inhibitors-alzheimers-disease-current-challenges-and-future-perspectives