{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:47:45Z","timestamp":1779119265542,"version":"3.51.4"},"reference-count":37,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2008,8,1]],"date-time":"2008-08-01T00:00:00Z","timestamp":1217548800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2008,8,1]],"date-time":"2008-08-01T00:00:00Z","timestamp":1217548800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["jpet.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"published-print":{"date-parts":[[2008,8]]},"DOI":"10.1124\/jpet.108.138974","type":"journal-article","created":{"date-parts":[[2008,5,23]],"date-time":"2008-05-23T00:53:24Z","timestamp":1211504004000},"page":"502-513","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":38,"title":["P-Glycoprotein Efflux and Other Factors Limit Brain Amyloid \u03b2 Reduction by \u03b2-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitors in Mice"],"prefix":"10.1016","volume":"326","author":[{"suffix":"Jr.","given":"Jere E.","family":"Meredith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorin A.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy H.","family":"Toyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence","family":"Marcin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna M.","family":"Barten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jovita","family":"Marcinkeviciene","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Kopcho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Guss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Burton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence","family":"Iben","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig","family":"Polson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Cantone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Ford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Drexler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracey","family":"Fiedler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberley A.","family":"Lentz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"James E.","family":"Grace","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Corsa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Pierdomenico","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelli","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E.","family":"Olson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John E.","family":"Macor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles F.","family":"Albright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1124\/jpet.108.138974_bib1","doi-asserted-by":"crossref","unstructured":"Artursson P, Palm K, and Luthman K (2001) Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 46: 27\u201343.","DOI":"10.1016\/S0169-409X(00)00128-9"},{"key":"10.1124\/jpet.108.138974_bib2","doi-asserted-by":"crossref","unstructured":"Asai M, Hattori C, Iwata N, Saido TC, Sasagawa N, Szabo B, Hashimoto Y, Maruyama K, Tanuma S, Kiso Y, et al. (2006) The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. J Neurochem 96: 533\u2013540.","DOI":"10.1111\/j.1471-4159.2005.03576.x"},{"key":"10.1124\/jpet.108.138974_bib3","doi-asserted-by":"crossref","unstructured":"Balimane PV, Han YH, and Chong S (2006) Current industrial practices of assessing permeability and P-glycoprotein interaction. AAPS J 8: E1\u2013E13.","DOI":"10.1208\/aapsj080101"},{"key":"10.1124\/jpet.108.138974_bib4","doi-asserted-by":"crossref","unstructured":"Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, Robertson BJ, et al. (2005) Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther 312: 635\u2013643.","DOI":"10.1124\/jpet.104.075408"},{"key":"10.1124\/jpet.108.138974_bib5","doi-asserted-by":"crossref","unstructured":"Best JD, Jay MT, Otu F, Ma J, Nadin A, Ellis S, Lewis HD, Pattison C, Reilly M, Harrison T, et al. (2005) Quantitative measurement of changes in amyloid-{beta}(40) in the rat brain and cerebrospinal fluid following treatment with the {gamma}-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-ox o-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl]-L-alaninamide]. J Pharmacol Exp Ther 313: 902\u2013908.","DOI":"10.1124\/jpet.104.081174"},{"key":"10.1124\/jpet.108.138974_bib6","doi-asserted-by":"crossref","unstructured":"Buxbaum JD, Thinakaran G, Koliatsos V, O\u2019Callahan J, Slunt HH, Price DL, and Sisodia SS (1998) Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J Neurosci 18: 9629\u20139637.","DOI":"10.1523\/JNEUROSCI.18-23-09629.1998"},{"key":"10.1124\/jpet.108.138974_bib7","doi-asserted-by":"crossref","unstructured":"Chang WP, Koelsch G, Wong S, Downs D, Da H, Weerasena V, Gordon B, Devasamudram T, Bilcer G, Ghosh AK, et al. (2004) In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors. J Neurochem 89: 1409\u20131416.","DOI":"10.1111\/j.1471-4159.2004.02452.x"},{"key":"10.1124\/jpet.108.138974_bib8","doi-asserted-by":"crossref","unstructured":"Cirrito JR, May PC, O\u2019Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, et al. (2003) In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23: 8844\u20138853.","DOI":"10.1523\/JNEUROSCI.23-26-08844.2003"},{"key":"10.1124\/jpet.108.138974_bib9","doi-asserted-by":"crossref","unstructured":"DeMattos RB, Bales KR, Cummins DJ, Paul SM, and Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer\u2019s disease. Science 295: 2264\u20132267.","DOI":"10.1126\/science.1067568"},{"key":"10.1124\/jpet.108.138974_bib10","doi-asserted-by":"crossref","unstructured":"Ford MJ, Cantone JL, Polson C, Toyn JH, Meredith JE, and Drexler DM (2008) Qualitative and quantitative characterization of the amyloid beta peptide (Abeta) population in biological matrices using an immunoprecipitation-LC\/MS assay. J Neurosci Methods 168: 465\u2013474.","DOI":"10.1016\/j.jneumeth.2007.11.019"},{"key":"10.1124\/jpet.108.138974_bib11","doi-asserted-by":"crossref","unstructured":"Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, and Yan R (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9: 1520\u20131525.","DOI":"10.1038\/nn1797"},{"key":"10.1124\/jpet.108.138974_bib12","doi-asserted-by":"crossref","unstructured":"Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman PJ, Growdon JH, and Selkoe DJ (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem 268: 22959\u201322962.","DOI":"10.1016\/S0021-9258(19)49409-X"},{"key":"10.1124\/jpet.108.138974_bib13","doi-asserted-by":"crossref","unstructured":"Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, Buck T, Walter D, Demont E, Howes C, et al. (2007) Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo. J Neurochem 100: 802\u2013809.","DOI":"10.1111\/j.1471-4159.2006.04260.x"},{"key":"10.1124\/jpet.108.138974_bib14","doi-asserted-by":"crossref","unstructured":"Kobayashi D, Zeller M, Cole T, Buttini M, McConlogue L, Sinha S, Freedman S, Morris RG, and Chen KS (2008) BACE1 gene deletion: impact on behavioral function in a model of Alzheimer\u2019s disease. Neurobiol Aging 29: 861\u2013873.","DOI":"10.1016\/j.neurobiolaging.2007.01.002"},{"key":"10.1124\/jpet.108.138974_bib15","doi-asserted-by":"crossref","unstructured":"Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang H-C, Xu G, Koliatsos VE, et al. (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25: 11693\u201311709.","DOI":"10.1523\/JNEUROSCI.2766-05.2005"},{"key":"10.1124\/jpet.108.138974_bib16","doi-asserted-by":"crossref","unstructured":"Lin JH (2008) CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab 9: 46\u201359.","DOI":"10.2174\/138920008783331077"},{"key":"10.1124\/jpet.108.138974_bib17","doi-asserted-by":"crossref","unstructured":"L\u00f6scherW and Potschka H (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76: 22\u201376.","DOI":"10.1016\/j.pneurobio.2005.04.006"},{"key":"10.1124\/jpet.108.138974_bib18","doi-asserted-by":"crossref","unstructured":"Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, and Polli JW (2002) Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303: 1029\u20131037.","DOI":"10.1124\/jpet.102.039255"},{"key":"#cr-split#-10.1124\/jpet.108.138974_bib19.1","unstructured":"Marcin LR and Lawrence R (2007) inventors"},{"key":"#cr-split#-10.1124\/jpet.108.138974_bib19.2","unstructured":"Bristol-Myers Squibb Co., assignee. Macrocyclic diaminopropanes as beta-secretase inhibitors. U.S. patent application US20070037868. 2007 Feb 15."},{"key":"10.1124\/jpet.108.138974_bib20","doi-asserted-by":"crossref","unstructured":"Matsuoka Y, Saito M, LaFrancois J, Gaynor K, Olm V, Wang L, Casey E, Lu Y, Shiratori C, Lemere C, et al. (2003) Novel therapeutic approach for the treatment of Alzheimer\u2019s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 23: 29\u201333.","DOI":"10.1523\/JNEUROSCI.23-01-00029.2003"},{"key":"10.1124\/jpet.108.138974_bib21","doi-asserted-by":"crossref","unstructured":"Nishitomi K, Sakaguchi G, Horikoshi Y, Gray AJ, Maeda M, Hirata-Fukae C, Becker AG, Hosono M, Sakaguchi I, Minami SS, et al. (2006) BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J Neurochem 99: 1555\u20131563.","DOI":"10.1111\/j.1471-4159.2006.04178.x"},{"key":"10.1124\/jpet.108.138974_bib22","doi-asserted-by":"crossref","unstructured":"Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, Vassar R, and Disterhoft JF (2006) Temporal memory deficits in Alzheimer\u2019s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23: 251\u2013260.","DOI":"10.1111\/j.1460-9568.2005.04551.x"},{"key":"10.1124\/jpet.108.138974_bib23","doi-asserted-by":"crossref","unstructured":"Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, and Vassar R (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP\/PS1 transgenic mice. Neurobiol Dis 26: 134\u2013145.","DOI":"10.1016\/j.nbd.2006.12.008"},{"key":"10.1124\/jpet.108.138974_bib24","doi-asserted-by":"crossref","unstructured":"Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, and Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer\u2019s disease. Neuron 41: 27\u201333.","DOI":"10.1016\/S0896-6273(03)00810-9"},{"key":"10.1124\/jpet.108.138974_bib25","doi-asserted-by":"crossref","unstructured":"Sankaranarayanan S, Price EA, Wu G, Crouthamel MC, Shi XP, Tugusheva K, Tyler KX, Kahana J, Ellis J, Jin L, et al. (2008) In vivo beta-secretase 1 inhibition leads to brain Abeta lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1. J Pharmacol Exp Ther 324: 957\u2013969.","DOI":"10.1124\/jpet.107.130039"},{"key":"10.1124\/jpet.108.138974_bib26","doi-asserted-by":"crossref","unstructured":"Selkoe DJ (2001) Alzheimer\u2019s disease: genes, proteins, and therapy. Physiol Rev 81: 741\u2013766.","DOI":"10.1152\/physrev.2001.81.2.741"},{"key":"10.1124\/jpet.108.138974_bib27","doi-asserted-by":"crossref","unstructured":"Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, and Oltersdorf T (1988) Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A 85: 7341\u20137345.","DOI":"10.1073\/pnas.85.19.7341"},{"key":"10.1124\/jpet.108.138974_bib28","doi-asserted-by":"crossref","unstructured":"Shen DW, Cardarelli C, Hwang J, Cornwell M, Richert N, Ishii S, Pastan I, and Gottesman MM (1986) Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J Biol Chem 261: 7762\u20137770.","DOI":"10.1016\/S0021-9258(19)57466-X"},{"key":"10.1124\/jpet.108.138974_bib29","doi-asserted-by":"crossref","unstructured":"Smalley J, Marino AM, Xin B, Olah T, and Balimane PV (2007) Development of a quantitative LC-MS\/MS analytical method coupled with turbulent flow chromatography for digoxin for the in vitro P-gp inhibition assay. J Chromatogr B Analyt Technol Biomed Life Sci 854: 260\u2013267.","DOI":"10.1016\/j.jchromb.2007.04.030"},{"key":"10.1124\/jpet.108.138974_bib30","doi-asserted-by":"crossref","unstructured":"Stachel SJ, Coburn CA, Sankaranarayanan S, Price EA, Wu G, Crouthamel M, Pietrak BL, Huang Q, Lineberger J, Espeseth AS, et al. (2006) Macrocyclic inhibitors of beta-secretase: functional activity in an animal model. J Med Chem 49: 6147\u20136150.","DOI":"10.1021\/jm060884i"},{"key":"10.1124\/jpet.108.138974_bib31","doi-asserted-by":"crossref","unstructured":"Stauffer SR, Stanton MG, Gregro AR, Steinbeiser MA, Shaffer JR, Nantermet PG, Barrow JC, Rittle KE, Collusi D, Espeseth AS, et al. (2007) Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Lett 17: 1788\u20131792.","DOI":"10.1016\/j.bmcl.2006.12.051"},{"key":"#cr-split#-10.1124\/jpet.108.138974_bib32.1","unstructured":"Thompson LA 3rd, Boy KM, Shi J, and Macor JE (2006) inventors"},{"key":"#cr-split#-10.1124\/jpet.108.138974_bib32.2","unstructured":"Bristol-Myers Squibb Company, assignee. Novel gamma-lactams as beta-secretase inhibitors. U.S. patent application 20060046984. 2006 Mar 2."},{"key":"10.1124\/jpet.108.138974_bib33","doi-asserted-by":"crossref","unstructured":"Vassar R (2002) Beta-secretase (BACE) as a drug target for Alzheimer\u2019s disease. Adv Drug Deliv Rev 54: 1589\u20131602.","DOI":"10.1016\/S0169-409X(02)00157-6"},{"key":"10.1124\/jpet.108.138974_bib34","doi-asserted-by":"crossref","unstructured":"Walsh DM and Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer\u2019s disease. Neuron 44: 181\u2013193.","DOI":"10.1016\/j.neuron.2004.09.010"},{"key":"10.1124\/jpet.108.138974_bib35","doi-asserted-by":"crossref","unstructured":"Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, and Haass C (2006) Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314: 664\u2013666.","DOI":"10.1126\/science.1132341"}],"container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524345458?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524345458?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1124\/jpet.108.138974","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T22:42:44Z","timestamp":1740004964000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022356524345458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8]]},"references-count":37,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2008,8]]}},"alternative-id":["S0022356524345458"],"URL":"https:\/\/doi.org\/10.1124\/jpet.108.138974","relation":{},"ISSN":["0022-3565"],"issn-type":[{"value":"0022-3565","type":"print"}],"subject":[],"published":{"date-parts":[[2008,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"P-Glycoprotein Efflux and Other Factors Limit Brain Amyloid \u03b2 Reduction by \u03b2-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitors in Mice","name":"articletitle","label":"Article Title"},{"value":"The Journal of Pharmacology and Experimental Therapeutics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1124\/jpet.108.138974","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2008 The American Society for Pharmacology and Experimental Therapeutics","name":"copyright","label":"Copyright"}]}}