Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease

Introduction: In an attempt of altering the natural history of Alzheimer's disease (AD), several compounds have been developed with the aim of inhibiting gamma-secretase, the enzymatic complex generating beta-amyloid (A beta) peptides (A beta(1 - 40) and A beta(1 - 42)), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiological cascade of AD. Areas covered: This article briefly reviews the profile of gamma-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on gamma-secretase inhibitors published before November 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting beta-amyloid, gamma-secretase inhibitors, dementia syndromes and Alzheimer's disease. Expert opinion: Studies in both transgenic and non-transgenic animal models of AD have indicated that gamma-secretase inhibitors, administered by the oral route, are able to lower brain A beta concentrations. However, scanty data are available on the effects of these compounds on brain A beta deposition after prolonged administration. gamma-Secretase inhibitors may cause significant toxicity in experimental animals and in humans believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective gamma-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.