Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.

The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1′ region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2′ substituent of chromane–HEA(s) with polar substituents provided improvements in the compound’s in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.