Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

Sandgren , Veronica; Belda , Oscar; Kvarnström , Ingemar; Lindberg , Jimmy; Samuelsson , Bertil; Dahlgren , Anders

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

Veronica Sandgren ¹, Oscar Belda ², Ingemar Kvarnström ¹, Jimmy Lindberg ², Bertil Samuelsson ², Anders Dahlgren ^{1, *}

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

² Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden

Article Information

Identifiers and Pagination:

Year: 2015
Volume: 9
First Page: 13
Last Page: 26
Publisher ID: TOMCJ-9-13
DOI: 10.2174/1874104501509010013

Article History:

Received Date: 1/10/2014
Revision Received Date: 6/1/2015
Acceptance Date: 22/1/2015
Electronic publication date: 17 /4/2015
Collection year: 2015

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© Sandgren et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

^* Address correspondence to this author at the Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden; Tel: +46 13 281000; Fax: +46 13 281399; E-mail: andda@ifm.liu.se

A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.

Keywords: Alzheimer’s disease, BACE-1 inhibition, cellular permeability, macrocycles, ring-closing metathesis, X-ray structure.

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RESEARCH ARTICLE

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

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