Gamma-secretase modulation and its promise for Alzheimer's disease: a medicinal chemistry perspective

Abstract

Gamma-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 gamma secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-beta(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 gamma 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-beta(1-42) peptide production. In addition, a very limited number of non-NSAID derived gamma 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 gamma-secretase.