Synthesis and structure–activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors

A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for β-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC50 constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood–brain barrier.

Graphical abstractA library of 1,3-disubstituted 2-propanols was synthesized and tested as BACE-1 inhibitors. The compound with best activity was subjected to SAR studies to develop a nanomolar inhibitor with excellent selectivity over cathepsin D and predicted physicochemical properties optimal to penetrate BBB.Figure optionsDownload full-size imageDownload as PowerPoint slide