The Design and Optimization of 3-OH Anthranilate Analogues as Amyloid-Beta Antiaggregants: A Mechanism of Action Study on a Novel Class of Potential Therapeutics for Alzheimer's Disease

Accounting for 100,000 deaths annually, Alzheimer's disease (AD) is the fourth leading cause of deaths in North America, surpassed only by heart disease, cancer and stroke. Existing treatments for AD fail to address the underlying causes of disease progression, and merely provide short-term relief from the symptoms of the disease. The amyloid hypothesis of AD implicates amyloid-beta (ABeta) protein misfolding as the root of the disease. Small clumps of ABeta have been shown to be toxic to the brain in AD. As such, preventing the formation of these clumps of ABeta may prevent brain damage - addressing the underlying disease cause, thereby preventing AD altogether; not merely masking the disease symptoms. Using computer modeling we have identified the molecule 3-OH anthranilate (HOA) as a potent antiaggregant - a preventer of ABeta clump formation - and may be a potential AD therapeutic; these results were confirmed using biological testing. Using HOA as a starting point, over 25 similar molecules have been synthesized - 9 of which have are even better antiaggregants. These molecules provide insight into future drug-like molecules that will be synthesized and tested. Over 50 HOA-like molecules have been tested for antiaggregant activity. To better understand how these drug-like molecules interact with ABeta we are to conduct studies using nuclear magnetic resonance spectroscopy. Diffusion spectroscopy will be used to investigate molecule-protein interactions. These experiments will provide better insight into the nature of these interactions and will allow us to optimize our computer models; in doing so we will be better able to use our computer models to predict the structure of more potent antiaggregants. With further optimization these new molecules are a starting point for potential drugs to be used in the treatment of Alzheimer's disease. Ultimately we wish to develop a new class of molecules to be used as AD therapeutics.