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

Abstract The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P 1′ region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P 2′ 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.