文摘
Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer鈥檚 disease. Synthetic methods, crystal structures, and structure鈥揳ctivity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in A尾40 and A尾42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain A尾 was 40鈥?0%, 1.5 h after oral dosing (100 渭mol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.