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

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

doi:10.2174/1874104501509010013

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

Open Med Chem J. 2015 Mar 31:9:13-26. doi: 10.2174/1874104501509010013. eCollection 2015.

Authors

Veronica Sandgren¹, Oscar Belda², Ingemar Kvarnström¹, Jimmy Lindberg², Bertil Samuelsson², Anders Dahlgren¹

Affiliations

¹ Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
² Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.

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; X-ray structure.; cellular permeability; macrocycles; ring-closing metathesis.