title: P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice.
abstract: 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.
authors.affiliation: Research and Development, Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT, USA. jere.meredith@bms.com
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.forename: Lawrence
authors.initials: L
authors.lastname: Marcin
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Jovita
authors.initials: J
authors.lastname: Marcinkeviciene
authors.forename: Lisa
authors.initials: L
authors.lastname: Kopcho
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
authors.forename: Alan
authors.initials: A
authors.lastname: Lin
authors.forename: Valerie
authors.initials: V
authors.lastname: Guss
authors.forename: Catherine
authors.initials: C
authors.lastname: Burton
authors.forename: Lawrence
authors.initials: L
authors.lastname: Iben
authors.forename: Craig
authors.initials: C
authors.lastname: Polson
authors.forename: Joe
authors.initials: J
authors.lastname: Cantone
authors.forename: Michael
authors.initials: M
authors.lastname: Ford
authors.forename: Dieter
authors.initials: D
authors.lastname: Drexler
authors.forename: Tracey
authors.initials: T
authors.lastname: Fiedler
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: James E
authors.initials: JE
authors.lastname: Grace
authors.forename: Janet
authors.initials: J
authors.lastname: Kolb
authors.forename: Jason
authors.initials: J
authors.lastname: Corsa
authors.forename: Maria
authors.initials: M
authors.lastname: Pierdomenico
authors.forename: Kelli
authors.initials: K
authors.lastname: Jones
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
mesh_terms: 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
chemical_list: 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