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

Sandgren, Veronica; Agback, Tatiana; Johansson, Per-Ola; Lindberg, Jimmy; Kvarnstrom, Ingemar; Samuelsson, Bertil; Belda, Oscar; Dahlgren, Anders

doi:10.1016/j.bmc.2012.05.039

Research article2012Peer reviewedOpen access

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

Sandgren, Veronica; Agback, Tatiana; Johansson, Per-Ola; Lindberg, Jimmy; Kvarnstrom, Ingemar; Samuelsson, Bertil; Belda, Oscar; Dahlgren, Anders

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 to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed. (C) 2012 Elsevier Ltd. All rights reserved.

Keywords

Alzheimer's disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere

Published in

Bioorganic and Medicinal Chemistry
2012, Volume: 20, number: 14, pages: 4377-4389 Publisher: PERGAMON-ELSEVIER SCIENCE LTD

UKÄ Subject classification

Medicinal Chemistry

Publication identifier

DOI: https://doi.org/10.1016/j.bmc.2012.05.039

Permanent link to this page (URI)

https://res.slu.se/id/publ/99462