Abstract
Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression. According to the “Amyloid Cascade Hypothesis” the critical molecular event in the pathogenesis of AD is the accumulation of Aβ neurotoxic oligomers. Since the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) is the rate-limiting step in the production of Aβ, this enzyme is considered a major therapeutic target and BACE1 inhibitors have the potential to be disease-modifying drugs for AD treatment. Therefore, intensive efforts to discover and develop inhibitors that can reach the brain and effectively inhibit BACE1 have been pursued by several groups worldwide. The aim of this review is to highlight the progress in the discovery of potent and selective small molecule BACE1 inhibitors over the past decade.
Highlights
Dementia has a tremendous emotional impact on the individual and his family, as well as an immense percussion at the economic level
Essential areas to cognitive processes in the brain are damaged during the disease development, leading to early synapse loss, neuronal dysfunction, and death culminating in brain atrophy, which are responsible for the manifestation of the disease (Querfurth and LaFerla, 2010)
These neurotoxic agents may interact with many neuronal receptors triggering a neurodegenerative cascade of events that are responsible for mitochondria dysfunction (Hauptmann et al, 2006; Carvalho et al, 2015), endoplasmic reticulum stress (Correia et al, 2015; Plácido et al, 2015), oxidative stress (Carvalho et al, 2016), DNA damage, neuroinflammation, among other deleterious mechanisms
Summary
Dementia has a tremendous emotional impact on the individual and his family, as well as an immense percussion at the economic level. Small molecule derivatives with aminohydantoin scaffold have been reported as BACE1 inhibitors, including the disubstituted pyridinyl aminohydantoins with low nanomolar potency and high selectivity for BACE1 (Malamas et al, 2010a,b,c, 2011; Zhou et al, 2010) and the small and rigid spirocyclic aminohydantoin analogs, which were designed through a structure-activity relationship (SAR) approach to improve their in vivo activity (Hunt et al, 2013).
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