American Chemical Society
jm6b01173_si_001.pdf (696.22 kB)

Discovery of N‑(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer’s Disease

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journal contribution
posted on 2017-01-20, 00:00 authored by Frederik J. R. Rombouts, José-Ignacio Andrés, Manuela Ariza, José Manuel Alonso, Nigel Austin, Astrid Bottelbergs, Lu Chen, Vladimir Chupakhin, Erna Cleiren, Katleen Fierens, Alberto Fontana, Xavier Langlois, Joseph E. Leenaerts, Jonas Mariën, Carolina Martínez Lamenca, Rhys Salter, Mark E. Schmidt, Paula Te Riele, Cindy Wintmolders, Andrés A. Trabanco, Wei Zhang, Gregor Macdonald, Dieder Moechars
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.