γ-Secretase Modulation and its Promise for Alzheimer's Disease: a Medicinal Chemistry Perspective

γ-Secretase modulation holds the promise for the development of a disease-modifying therapy for Alzheimer's disease (AD). This novel concept of manipulating the cleavage specificity of the γ-secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-β(1-42) peptide can be lowered without the undesired side effects associated with full inhibition of this aspartyl-type protease. Following on from the initial discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) exhibit properties characteristic of γ-secretase modulators, this class of compounds has been extensively studied and exploited, leading to the discovery of NSAIDs derivatives endowed with improved potency for the reduction of amyloid-β(1-42) peptide production. In addition, a very limited number of non-NSAID derived γ-secretase modulators has also been recently claimed in the patent literature, suggesting that only a restricted number of pharmacophores might be involved in the modulation of γ-secretase.