First Demonstration of Cerebrospinal Fluid and Plasma Aβ Lowering with Oral Administration of a β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor in Nonhuman Primates
| العنوان: | First Demonstration of Cerebrospinal Fluid and Plasma Aβ Lowering with Oral Administration of a β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor in Nonhuman Primates |
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| المؤلفون: | Janet Lineberger, Matthew G. Stanton, Amy S. Espeseth, Beth Pietrak, Min Xu, Katherine Tugusheva, Harold G. Selnick, Dennis Colussi, Guy R. Seabrook, John Swestock, Jason Kahana, Ming-Chih Crouthamel, Viswanath Devanarayan, Keala X. Tyler, Guoxin Wu, Daria J. Hazuda, Shaun R. Stauffer, Joan D. Ellis, Marie A. Holahan, Joseph P. Vacca, Philippe G. Nantermet, Melissa A. Steinbeiser, Georgia B. McGaughey, Eric A. Price, Jerome Hochman, Hemaka A. Rajapakse, Sethu Sankaranarayanan, Adam J. Simon, Samuel L. Graham, Keith P. Moore, M. Katharine Holloway, Ming-Tain Lai, Lixia Jin, Adam Gates, Xiao-Ping Shi, Jacky Wong, Jacquelynn J. Cook, Allison R. Gregro |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 328:131-140 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | medicine.medical_specialty, Membrane permeability, Mice, Transgenic, Pharmacology, Transfection, Cisterna magna, Amyloid beta-Protein Precursor, Mice, Cerebrospinal fluid, Pharmacokinetics, Oral administration, In vivo, Internal medicine, medicine, Amyloid precursor protein, Animals, Aspartic Acid Endopeptidases, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Enzyme Inhibitors, Infusions, Intravenous, biology, Macaca mulatta, Endocrinology, biology.protein, Molecular Medicine, Amyloid Precursor Protein Secretases, Amyloid precursor protein secretase |
| الوصف: | beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate. |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::01219a959e3def2dc15d6af0a2e96474Test https://doi.org/10.1124/jpet.108.143628Test |
| رقم الانضمام: | edsair.doi.dedup.....01219a959e3def2dc15d6af0a2e96474 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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