Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer’s Disease
| Autor: | Mark E. Schmidt, Rhys Salter, Cindy Wintmolders, Nigel Austin, Vladimir Chupakhin, Gregor James Macdonald, Astrid Bottelbergs, Paula te Riele, Lu Chen, Katleen Fierens, Diederik Moechars, Andrés A. Trabanco, José-Ignacio Andrés, José Manuel Alonso, Jonas Mariën, Erna Cleiren, Martinez Lamenca Carolina, Frederik J. R. Rombouts, Manuela Ariza, Leenaerts Joseph Elisabeth, Xavier Langlois, Wei Zhang, Alberto Fontana |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Tau pathology tau Proteins Protein aggregation Protein Aggregation Pathological Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Alzheimer Disease mental disorders Drug Discovery Animals Humans Naphthyridines Pet tracer Amination Amyloid beta-Peptides Chemistry Quinoline Brain Haplorhini Combinatorial chemistry First generation Rats 030104 developmental biology Positron-Emission Tomography Molecular Medicine Selectivity 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 60:1272-1291 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01173 |
| Popis: | A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer. |
| Databáze: | OpenAIRE |
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