SAR of tertiary carbinamine derived BACE1 inhibitors: Role of aspartate ligand amine pKa in enzyme inhibition

This Letter describes SAR of the tertiary carbinamine derived inhibitors of BACE1 revealed during the optimization of the unstable lead toward potent and stable heterocycle linked compounds. The incorporation of a flap interaction with the target enzyme was not critical for potency. A trend observed during this optimization was that the pKa of the amine derived aspartate ligand needed to be at least close to that of the assay medium for BACE1 inhibition.