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, *
Identifiers and Pagination:Year: 2015
First Page: 13
Last Page: 26
Publisher Id: TOMCJ-9-13
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
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.
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.