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* Pages 131 - 148 ( 18 )
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.
BACE-1 inhibitors, Alzheimer's disease, neurodegeneration, therapeutic agents, NFTs, N-methyl-D-aspartate.