Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy

The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compound 14 and compound 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds are discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo and 1.5 h after oral administration of 300 μmol/kg and efflux inhibitor GF120918 to wild type mice the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%.