Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360
| العنوان: | Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360 |
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| المؤلفون: | Jean-Michel Rondeau, Heinrich Rueeger, Rainer Martin Lueoend, Laura H. Jacobson, Markus Voegtle, Rainer Machauer, Grit Laue, Philipp Holzer, Konstanze Hurth, Siem Jacob Veenstra, Matthias Staufenbiel, Marina Tintelnot-Blomley, Ulf Neumann, Mathias Frederiksen |
| المصدر: | Journal of Medicinal Chemistry. 64:4677-4696 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Central nervous system, Thiazines, Molecular Dynamics Simulation, Pharmacology, Crystallography, X-Ray, 01 natural sciences, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Dogs, Alzheimer Disease, Oxazines, Drug Discovery, medicine, Animals, Aspartic Acid Endopeptidases, Humans, Potency, Enzyme Inhibitors, Picolinic Acids, 030304 developmental biology, 0303 health sciences, Amyloid beta-Peptides, Binding Sites, Trifluoromethyl, Treatment regimen, Brain, Penetration (firestop), Rats, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, chemistry, β secretase, Molecular Medicine, Efflux, Amyloid Precursor Protein Secretases, Lead compound, Half-Life |
| الوصف: | Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::71a0b16d3116f2d6a82dc5a3b35b580c https://doi.org/10.1021/acs.jmedchem.0c02143 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....71a0b16d3116f2d6a82dc5a3b35b580c |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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