P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice.
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.
Meredith
Jere E
JE
Research and Development, Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT, USA. jere.meredith@bms.com
Thompson
Lorin A
LA
Toyn
Jeremy H
JH
Marcin
Lawrence
L
Barten
Donna M
DM
Marcinkeviciene
Jovita
J
Kopcho
Lisa
L
Kim
Young
Y
Lin
Alan
A
Guss
Valerie
V
Burton
Catherine
C
Iben
Lawrence
L
Polson
Craig
C
Cantone
Joe
J
Ford
Michael
M
Drexler
Dieter
D
Fiedler
Tracey
T
Lentz
Kimberley A
KA
Grace
James E
JE
Kolb
Janet
J
Corsa
Jason
J
Pierdomenico
Maria
M
Jones
Kelli
K
Olson
Richard E
RE
Macor
John E
JE
Albright
Charles F
CF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse