Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

…, J Lindberg, I Kvarnström, B Samuelsson…

Index: Sandgren, Veronica; Agback, Tatiana; Johansson, Per-Ola; Lindberg, Jimmy; Kvarnstroem, Ingemar; Samuelsson, Bertil; Belda, Oscar; Dahlgren, Anders Bioorganic and Medicinal Chemistry, 2012 , vol. 20, # 14 p. 4377 - 4389

Full Text: HTML

Citation Number: 11

Abstract

A series of P1–P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N- phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt ...