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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 , *
Authors Info & Affiliations
Authors Info & Affiliations
The Open Medicinal Chemistry Journal
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17
Apr 2015 •
RESEARCH ARTICLE
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DOI: 10.2174/1874104501509010013
Abstract
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.
