Title:BACE-1 Inhibitors Targeting Alzheimer's Disease
Volume: 20
Issue: 3
Author(s): Kadja Luana Chagas Monteiro, Marcone Gomes dos Santos Alcântara, Nathalia Monteiro Lins Freire, Esaú Marques Brandão, Vanessa Lima do Nascimento, Líbni Maísa dos Santos Viana, Thiago Mendonça de Aquino and Edeildo Ferreira da Silva-Júnior*
Affiliation:
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival
Melo Mota Avenue, 57072-970, Maceió, Alagoas, Brazil
Keywords:
BACE-1 inhibitors, Alzheimer's disease, neurodegeneration, therapeutic agents, NFTs, N-methyl-D-aspartate.
Abstract: The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD)
progression. Over the years, several disease-modulating approaches have been reported, but without
clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau
protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme
1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release
the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage.
In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal
chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results
of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting
the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The
current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other
class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is
to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.
