Discovery of aminoheterocycles as a novel β-secretase inhibitor class: pH dependence on binding activity part 1

We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pKa of these inhibitors and the pH of the BACE-1 enzyme binding assay.

Graphical abstractA novel series of heteroaromatic BACE-1 inhibitors is described. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, a pH dependent effect on the binding affinity as a result of the intrinsic pKa of these inhibitors and the pH of the BACE-1 enzyme binding assay is discussed.Figure optionsDownload full-size imageDownload as PowerPoint slide