Inhibitors of Aβ production: solid-phase synthesis and SAR of α-hydroxycarbonyl derivatives

Inhibitors of amyloid-β (Aβ) protein production have been widely pursued as a potential treatment for Alzheimerʹs disease. Following the identification of a 5 μM screening hit, SAR was initiated using solid-phase synthetic techniques. Two series of α-hydroxy esters and ketones which are sub-micromolar inhibitors of Aβ production were identified. The most potent α-hydroxyketone identified is approximately 30-fold more potent than the initial lead.