γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs

Journal of Medicinal Chemistry
2011.0

Abstract

Alzheimer's disease (ADa ) is an incurable degenerative disease that was first described by the German psychiatrist and neuropathologist Alois Alzheimer in 1906, from whom it takes its name. He reported the existence of two abnormal structures, senile plaques and neurofibrillary tangles, in the brain of his patient Auguste D., who was suffering from dementia.1 AD is an age-related neurodegenerative disorder, which progresses through symptoms including confusion, aggression, irritability, loss of vocal and motor control, longand short-term memory loss, and gradual loss of bodily functions, which ultimately results in death.2More than 26 million people worldwide suffer from AD, and a recent estimate predicts that this number will quadruple by 2050 to more than 106 million.3 To date, the disease therapeutics consists of just five FDA approved drugs, which only treat cognitive decline and negative symptoms of the disease. The drugs fall into two classes: the first four, donepezil, rivastigmine, tacrine, and galantamine, are acetylcholine esterase inhibitors, and the fifth most recent compound, memantine, is an NMDA antagonist.4Thus, the development of a treatment or cure for AD that may slow or reverse the progression of the disease in the form of a so-called "diseasemodifying anti-Alzheimer's drug" (DMAAD) represents a huge unmet medical, social, and economic need. The development of DMAADs relies on the understanding of the disease progression and pathway and on identifying the molecular targets of therapeutic interest.

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