New Aminoimidazoles as β‑Secretase (BACE-1) Inhibitors Showing Amyloid‑β (Aβ) Lowering in Brain

Abstract

Amino-2<i>H</i>-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer’s disease. Synthetic methods, crystal structures, and structure–activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (<i>S</i>)-<b>1m</b> 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 (<i>S</i>)-<b>1m</b>, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40–50%, 1.5 h after oral dosing (100 μmol/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