Title:BACE-1 Inhibitors Targeting Alzheimer's Disease
Volume: 20
Issue: 3
关键词:
BACE-1 抑制剂、阿尔茨海默病、神经变性、治疗剂、NFT、N-甲基-D-天冬氨酸。
摘要: 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.
