Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

The identification of small molecule aminoimidazoles as potent and selective human P-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show > 100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE I binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC(50) value for BACE1 of 20 nM, cellular activity of 90 nM, and > 100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma A beta(40) measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).