Recent developments of small molecule γ-secretase modulators for Alzheimer's disease

Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disorder, marked by memory loss and a decline in cognitive function. The major hallmarks of AD are the presence of intracellular neurofibrillary tau tangles (NFTs) composed of hyperphosphorylated tau proteins and extracellular plaques composed of amyloid beta peptides (Aβ). The amyloid (Aβ) cascade hypothesis proposes that the AD pathogenesis is initiated by the accumulation of Aβ peptides in the parenchyma of the brain. An aspartyl intramembranal protease called γ-secretase is responsible for the production of Aβ by the cleavage of the amyloid precursor protein (APP). Clinical studies of γ-secretase inhibitors (GSIs) for AD failed due to the lack of substrate specificity. Therefore, γ-secretase modulators (GSMs) have been developed as potential disease modifying agents to modulate the γ-secretase cleavage activity towards the production of toxic Aβ42 peptides. Following the first-generation 'nonsteroidal anti-inflammatory drug' (NSAID) based GSMs, second-generation GSMs (carboxylic acid based NSAID derivatives and non-NSAID derived heterocyclic analogues), as well as natural product-based GSMs, have been developed. In this review, we focus on the recent developments of small molecule-based GSMs that show potential improvements in terms of drug-like properties as well as their current status in human clinical trials and the future perspectives of GSM research.