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 (http://creativecommons.org/licenses/by/2.5/), 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: versa@ifm.liu.se,andda@ifm.liu.se


Abstract

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.