Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer's drug leads

We have identified highly selective imidazopyr-idines armed with benzimidazol and/or arylimidazole as potent β-secretase inhibitors. The most effective and selective analogues demonstrated low nanomolar potency for the BACE1 enzyme as measured by FRET and cell-based (ELISA) assays and exhibited comparable affinity (K _I) and high ligand efficiency (LE). In addition, these motifs were highly selective (>200) against the structurally related aspartyl protease BACE2. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported hydroxyethylene transition state inhibitor derived from iso-phthalic acid I. Of the most potent compounds, 34 displayed an IC ₅₀ for BACE1 of 18 nM and exhibited cellular activity with an EC ₅₀ of 37 nM in the cell-based ELISA assay, as well as high affinity (K _I = 17 nM) and ligand efficiency (LE = 1.7 kJ/mol). Compound 34 was found to be 204-fold more selective for BACE1 compared to the closely related aspartyl protease BACE2. (Figure presented)