1 research outputs found
Discovery of <i>N</i>ā(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimerās Disease
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 <i>N</i>-(6-methylpyridin-2-yl)Āquinolin-2-amine <b>10</b> as a novel potent binder to human AD aggregated tau with
modest selectivity versus aggregated Ī²-amyloid (AĪ²). 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 <b>75</b>, a potent and selective
tau aggregate binder with potential as a tau PET tracer