posted on 2017-01-20, 00:00authored byFrederik 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.