Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors.
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.
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Veronica
V
Sandgren
Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
Oscar
O
Belda
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Ingemar
I
Kvarnström
Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
Jimmy
J
Lindberg
Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
Bertil
B
Samuelsson
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Anders
A
Dahlgren
Alzheimer’s disease; BACE-1 inhibition; X-ray structure.; cellular permeability; macrocycles; ring-closing metathesis