Combining fatty acid amide hydrolase (FAAH) inhibition with peroxisome proliferator-activated receptor (PPAR) activation: a new potential multi-target therapeutic strategy for the treatment of Alzheimer's disease

[...]treatment with synthetic cannabinoids (mostly active on CB1, such as WIN55,212-2) and inhibitors of FAAH showed promising results in animal models of AD (Basavarajappa et al., 2017). In the recent years, researchers have been focusing on the synthesis and optimization of PPARα/γ dual agonists, PPARα/γ/δ pan-agonists, or even selective PPAR modulators capable of showing a different activity profile characterized by gene and tissue selective effects (Piemontese et al., 2015, 2017). [...]it was recently proposed that insulin resistance localized in the central nervous system might figure among the various pathogenic factors that contribute to the development of AD. Various known PPAR agonists show some structural similarity to Sobetirome and can be classified as 2-substituted phenoxyacetic acids, the main difference being some degree of steric hindrance on the alpha position of the carboxylic group (Piemontese et al., 2017). [...]the design of amides of these PPAR agonists could be an effective strategy to obtain central nervous system-directed pro-drugs of these compounds.