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

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

Bioorganic & medicinal chemistry (2012-06-16)
Veronica Sandgren, Tatiana Agback, Per-Ola Johansson, Jimmy Lindberg, Ingemar Kvarnström, Bertil Samuelsson, Oscar Belda, Anders Dahlgren
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ethylamine, 97%
Sigma-Aldrich
Ethylamine, 99.0%
Sigma-Aldrich
Ethylamine solution, 2.0 M in THF
Sigma-Aldrich
Ethylamine solution, 2.0 M in methanol
Sigma-Aldrich
Ethylamine solution, 66.0-72.0% in H2O