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Research ArticleNEUROPHARMACOLOGY

P-Glycoprotein Efflux and Other Factors Limit Brain Amyloid β Reduction by β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitors in Mice

Jere E. Meredith Jr., Lorin A. Thompson, Jeremy H. Toyn, Lawrence Marcin, Donna M. Barten, Jovita Marcinkeviciene, Lisa Kopcho, Young Kim, Alan Lin, Valerie Guss, Catherine Burton, Lawrence Iben, Craig Polson, Joe Cantone, Michael Ford, Dieter Drexler, Tracey Fiedler, Kimberley A. Lentz, James E. Grace Jr., Janet Kolb, Jason Corsa, Maria Pierdomenico, Kelli Jones, Richard E. Olson, John E. Macor and Charles F. Albright
Journal of Pharmacology and Experimental Therapeutics August 2008, 326 (2) 502-513; DOI: https://doi.org/10.1124/jpet.108.138974
Jere E. Meredith Jr.
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Lorin A. Thompson
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Jeremy H. Toyn
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Lawrence Marcin
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Donna M. Barten
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Jovita Marcinkeviciene
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Lisa Kopcho
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Young Kim
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Alan Lin
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Valerie Guss
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Catherine Burton
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Lawrence Iben
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Craig Polson
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Joe Cantone
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Michael Ford
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Dieter Drexler
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Tracey Fiedler
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Kimberley A. Lentz
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James E. Grace Jr.
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Janet Kolb
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Jason Corsa
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Maria Pierdomenico
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Kelli Jones
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Richard E. Olson
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John E. Macor
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid β (Aβ) 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, β-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 Aβ. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Aβ formation in cultured cells with IC50 values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Aβ peptides by mass spectrometry showed that these inhibitors decreased Aβ by inhibiting BACE1. An assay for Aβ1–40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Aβ1–40, but not brain Aβ1–40, 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 Aβ1–40 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 Aβ1–40 and brain Aβ1–40 dose responses for these three compounds revealed differences in relative ED50 values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.

Footnotes

  • J.E.Me. and L.A.T. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.138974.

  • ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid β; APP, amyloid precursor protein; BRACE1, β-site APP-cleaving enzyme 1; CTF, C-terminal fragment; KO, knockout; WT, wild type; P-gp, P-glycoprotein; compound A, (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-1-hydroxy-3-phenyl-1-((2R,4R)-4-(propylsulfonyl)pyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide; compound B, pentane-1-sulfonic acid ((1S,4R,5S,8S,14R)-5-benzyl-4-hydroxy-18-methoxy-7-oxo-13-oxa-2,6-diaza-tricyclo[12.6.1.015,20]henicosa-10,15(20),16,18-tetraen-8-yl)-methyl-amide; compound C, 3,3,3-trifluoro-propane-1-sulfonic acid [(1S,4R,5S,8S,15R)-5-(3,5-difluoro-benzyl)-4-hydroxy-19-methoxy-7-oxo-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-8-yl]-methyl-amide; HEK, human embryonic kidney; HEK-Wt, HEK cells stably expressing a wild-type human APP 695 transgene; HEK-Sw, HEK cells stably expressing a Swedish mutant of human APP 695 transgene; DMEM, Dulbecco's modified Eagle's medium; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; KBV-Sw, expression vector containing human APP751 with the Swedish mutation; ELISA, enzyme-linked immunosorbent assay; IP-LC/MS, immunoprecipitation in-line liquid chromatography mass spectrometry; dKO, BACE 1 and BACE2 double-KO mice; PBS, phosphate-buffered saline; NP-40, Nonidet P40; LC/MS/MS, liquid chromatography/tandem mass spectrometry; BMS-299897, 2-[(1R)-1-[[4-chlorophenyl)-sulfonyl](2,5-difluorophenyl)amino] ethyl]-5-fluoro-benzenepropanoic acid; Papp, apparent permeability in Caco-2 monolayers; B/P, brain to plasma ratio; CNS, central nervous system; [3H]BMS-599240, [3H](S)-2-((S)-3-acetylamino-3-sec-butyl-2-oxo-pyrrolidin-1-yl)-N-[(1S,R)-1-benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-4-phenyl-butyramide.

    • Received March 10, 2008.
    • Accepted May 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 326 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 326, Issue 2
1 Aug 2008
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Research ArticleNEUROPHARMACOLOGY

P-Glycoprotein Efflux and Other Factors Limit Brain Amyloid β Reduction by β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitors in Mice

Jere E. Meredith, Lorin A. Thompson, Jeremy H. Toyn, Lawrence Marcin, Donna M. Barten, Jovita Marcinkeviciene, Lisa Kopcho, Young Kim, Alan Lin, Valerie Guss, Catherine Burton, Lawrence Iben, Craig Polson, Joe Cantone, Michael Ford, Dieter Drexler, Tracey Fiedler, Kimberley A. Lentz, James E. Grace, Janet Kolb, Jason Corsa, Maria Pierdomenico, Kelli Jones, Richard E. Olson, John E. Macor and Charles F. Albright
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 502-513; DOI: https://doi.org/10.1124/jpet.108.138974

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Research ArticleNEUROPHARMACOLOGY

P-Glycoprotein Efflux and Other Factors Limit Brain Amyloid β Reduction by β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitors in Mice

Jere E. Meredith, Lorin A. Thompson, Jeremy H. Toyn, Lawrence Marcin, Donna M. Barten, Jovita Marcinkeviciene, Lisa Kopcho, Young Kim, Alan Lin, Valerie Guss, Catherine Burton, Lawrence Iben, Craig Polson, Joe Cantone, Michael Ford, Dieter Drexler, Tracey Fiedler, Kimberley A. Lentz, James E. Grace, Janet Kolb, Jason Corsa, Maria Pierdomenico, Kelli Jones, Richard E. Olson, John E. Macor and Charles F. Albright
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 502-513; DOI: https://doi.org/10.1124/jpet.108.138974
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