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

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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 ( 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:


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.