title: Alzheimer's disease: emerging trends in small molecule therapies.
abstract: 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 disease-modifying agents (DMAs).
authors.affiliation: School of Pharmacy, University of Waterloo, Health Sciences Campus, Waterloo, Ontario, CANADA N2L 3G1.
authors.forename: T
authors.initials: T
authors.lastname: Mohamed
authors.forename: P P N
authors.initials: PP
authors.lastname: Rao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D018679:Cholinergic Agonists / Q000737:chemistry / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D004358:Drug Therapy / Q000639:trends*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018679:Cholinergic Agonists; D002800:Cholinesterase Inhibitors; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D054852:Small Molecule Libraries; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases