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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. 2007 Feb; 100(3):802-9.JN

Abstract

Generation and deposition of the amyloid beta (Abeta) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and gamma-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Abeta, is an attractive therapeutic approach for the treatment of Alzheimer's disease. We have designed a selective non-peptidic BACE-1 inhibitor, GSK188909, that potently inhibits beta-cleavage of APP and reduces levels of secreted and intracellular Abeta in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain Abeta in vivo. In APP transgenic mice, acute oral administration of GSK188909 in the presence of a p-glycoprotein inhibitor to markedly enhance the exposure of GSK188909 in the brain decreases beta-cleavage of APP and results in a significant reduction in the level of Abeta40 and Abeta42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain Abeta. This pivotal first report of central Abeta lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease.

Authors+Show Affiliations

Neurology and GastroIntestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Ltd, Harlow, Essex, UK. Ishrut_2_Hussain@gsk.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17156133

Citation

Hussain, Ishrut, et al. "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." Journal of Neurochemistry, vol. 100, no. 3, 2007, pp. 802-9.
Hussain I, Hawkins J, Harrison D, et al. 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. 2007;100(3):802-9.
Hussain, I., Hawkins, J., Harrison, D., Hille, C., Wayne, G., Cutler, L., Buck, T., Walter, D., Demont, E., Howes, C., Naylor, A., Jeffrey, P., Gonzalez, M. I., Dingwall, C., Michel, A., Redshaw, S., & Davis, J. B. (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. Journal of Neurochemistry, 100(3), 802-9.
Hussain I, et al. 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. 2007;100(3):802-9. PubMed PMID: 17156133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Hussain,Ishrut, AU - Hawkins,Julie, AU - Harrison,David, AU - Hille,Christopher, AU - Wayne,Gareth, AU - Cutler,Leanne, AU - Buck,Tania, AU - Walter,Daryl, AU - Demont,Emmanuel, AU - Howes,Colin, AU - Naylor,Alan, AU - Jeffrey,Philip, AU - Gonzalez,Maria I, AU - Dingwall,Colin, AU - Michel,Anton, AU - Redshaw,Sally, AU - Davis,John B, PY - 2006/12/13/pubmed PY - 2007/3/21/medline PY - 2006/12/13/entrez SP - 802 EP - 9 JF - Journal of neurochemistry JO - J Neurochem VL - 100 IS - 3 N2 - Generation and deposition of the amyloid beta (Abeta) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and gamma-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Abeta, is an attractive therapeutic approach for the treatment of Alzheimer's disease. We have designed a selective non-peptidic BACE-1 inhibitor, GSK188909, that potently inhibits beta-cleavage of APP and reduces levels of secreted and intracellular Abeta in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain Abeta in vivo. In APP transgenic mice, acute oral administration of GSK188909 in the presence of a p-glycoprotein inhibitor to markedly enhance the exposure of GSK188909 in the brain decreases beta-cleavage of APP and results in a significant reduction in the level of Abeta40 and Abeta42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain Abeta. This pivotal first report of central Abeta lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/17156133/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_ L2 - https://doi.org/10.1111/j.1471-4159.2006.04260.x DB - PRIME DP - Unbound Medicine ER -