Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy.
The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300μmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%.
Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-15185 Södertälje, Sweden.
Britt-Marie
BM
Swahn
Jörg
J
Holenz
Jacob
J
Kihlström
Karin
K
Kolmodin
Johan
J
Lindström
Niklas
N
Plobeck
Didier
D
Rotticci
Fernando
F
Sehgelmeble
Marie
M
Sundström
Stefan von
Sv
Berg
Johanna
J
Fälting
Biljana
B
Georgievska
Susanne
S
Gustavsson
Jan
J
Neelissen
Margareta
M
Ek
Lise-Lotte
LL
Olsson
Stefan
S
Berg
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D000588:Amines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism
D000588:Amines; D016229:Amyloid beta-Peptides; D007093:Imidazoles; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse