Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.

Abstract Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P 2′ position of the inhibitor with more polar substituents led to compounds 19 and 32 , which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.