Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents

Veronica Sandgren*, Marcus Bäck, Ingemar Kvarnström , Anders Dahlgren
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden

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© Sandgren et al.; Licensee Bentham Open.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

* Address correspondence to this authors Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden; Tel: +46 13 281000; Fax: +46 13 281399; E-mails:,


Novel BACE-1 inhibitors with a hydroxyethylene central core have been developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e. 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.

Keywords: Alzheimer’s disease, BACE-1 inhibitors, extended P1 substituents, hydroxyethylene isosteres, P1´ modifications, S1-S3 pocket.