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

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

doi:10.1016/j.bmc.2012.05.039

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

Bioorg Med Chem. 2012 Jul 15;20(14):4377-89. doi: 10.1016/j.bmc.2012.05.039. Epub 2012 May 24.

Authors

Veronica Sandgren¹, Tatiana Agback, Per-Ola Johansson, Jimmy Lindberg, Ingemar Kvarnström, Bertil Samuelsson, Oscar Belda, Anders Dahlgren

Affiliation

¹ Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.

PMID: 22698785
DOI: 10.1016/j.bmc.2012.05.039

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 IC(50) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Binding Sites
Crystallography, X-Ray
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Ethylamines / chemical synthesis
Ethylamines / chemistry*
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Ethylamines
Amyloid Precursor Protein Secretases
ethylamine