Small-Molecule Amyloid Beta-Aggregation Inhibitors in Alzheimer's Disease Drug Development

Abstract

Alzheimer's disease (AD) is still an incurable neurodegenerative disease that causes dementia. AD changes the brain function that, over time, impairs memory and diminishes judgment and reasoning ability. Pathophysiology of AD is complex. Till now the cause of AD remains unknown, but risk factors include family history and genetic predisposition. The drugs previously approved for AD treatment do not modify the disease process and only provide symptomatic improvement. Over the past few decades, research has led to significant progress in the understanding of the disease, leading to several novel strategies that may modify the disease process. One of the major developments in this direction is the amyloid β (Aβ) aggregation. Small molecules could block the initial stages of Aβ aggregation, which could be the starting point for the design and development of new AD drugs in the near future. In this review we summarize the most promising small-molecule Aβ-aggregation inhibitors including natural compounds, novel small molecules, and also those are in clinical trials. Moreover, we briefly summarized some reported docking studies of small-molecule Aβ aggregation inhibitors. These will give us an idea about the chemical features required to design novel small molecules with anti-Aβ aggregation properties.

Neuroprotective effects on amyloid-beta induced cytotoxicity of Pandanus clementis Merr

“…Amyloid plaques are extracellular buildup in the brain contributed by the Aβ peptides (Sharma et al 2017) resulting in nerve cell death and tissue loss (Espargaró et al 2017), which eventually lead to cognitive and synaptic dysfunctions and neurodegeneration in AD (Sharma et al 2017). Hence, the discovery of potential Aβ aggregation inhibitors has attracted much attention in AD drug research (Battisti et al 2017;Giorgetti et al 2018;Chowdhury et al 2019;Phan et al 2019).…”

Nanomaterials in Alzheimer’s disease treatment: a comprehensive review

“…As an attempt to combat the AD, novel therapeutic approaches mainly the development of (i) small molecule inhibitors which blocks oligomerization step and (ii) catalytic antibodies for the hydrolysis of Aβ aggregates are devised [37]. Some of the US FDA approved medications used in the treatment of AD are donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) which comes under cholinesterase inhibitors while memantine (Namenda) affects glutamatergic system [38]. Contilisant, a neuroprotectant demonstrated significant inhibitory effects against monoamine oxidases and cholinesterases and also augments the cognitive functions impaired due to aggregation of Aβ 42 [39].…”

Modeling Inhibitory Effects of Chlorogenic Acid on Amyloid Beta Aggregation

“…7,12,17,18 Various classes of therapeutic molecules have been studied to treat AD, including small molecules, metal chelators, nanostructures, peptides (or peptide mimics), and antibodies. 19 Small molecule drugs generally pass the blood brain barrier, target specific pathways, 20 are easy to synthesize, and it is easy to elucidate their mechanisms of action. 21 Thus, these drugs can play a crucial role as Aβ-aggregation inhibitors to treat AD.…”