Inhibitors and modulators of beta- and gamma-secretase.

Most gene mutations associated with Alzheimer's disease point to the metabolism of amyloid precursor protein as potential cause. The beta- and gamma-secretases are two executioners of amyloid precursor protein processing resulting in amyloid beta. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for gamma-secretase. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. This review focuses on the developments since 2003.