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Alzheimer's Disease: Emerging Trends in Small Molecule Therapies

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Alzheimer's disease (AD) is a highly complex and rapidly progressive neurodegenerative disorder characterized by the systemic collapse of cognitive function and formation of dense amyloid plaques and neurofibrillary tangles. AD pathology is derived from the cholinergic, amyloid and tau hypotheses, respectively. Current pharmacotherapy with known anti-cholinesterases, such as Aricept® and Exelon®, only offer symptomatic relief without any disease-modifying effects. It is now clear that in order to prevent the rapid progression of AD, new therapeutic treatments should target multiple AD pathways as opposed to the traditional “one drug, one target” approach. This review will focus on the recent advances in medicinal chemistry aimed at the development of small molecule therapies that target various AD pathological routes such as the cholinesterases (AChE and BuChE), amyloidogenic secretases (β/γ- secretase), amyloid-β aggregation, tau phosphorylation and fibrillation and metal-ion redox/reactive oxygen species (ROS). Some notable ring templates will be discussed along with their structure-activity relationship (SAR) data and their multiple modes of action. These emerging trends signal a paradigm shift in anti-AD therapies aimed at the development of multifunctional small molecules as diseasemodifying agents (DMAs).

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Keywords: AD; Alzheimer's disease; amyloid plaques; amyloid precursor protein; cholinesterase; disease-modifying agents; neurofibrillary tangles; reactive oxygen species; tau protein; α/β/γ-secretase

Document Type: Research Article

Publication date: 01 October 2011

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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