文摘
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1¡ä region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2¡ä 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.