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

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

Graphical abstractThis 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.Figure optionsDownload full-size imageDownload as PowerPoint slide