BACE-1 Inhibitors Targeting Alzheimer's Disease

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.

Keywords: Alzheimer's disease; BACE-1 inhibitors; N-methyl-D-aspartate; NFTs; neurodegeneration; therapeutic agents.