2 research outputs found
Pyrido[4,3ā<i>e</i>][1,2,4]triazolo[4,3ā<i>a</i>]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors
A novel
series of pyridoĀ[4,3-<i>e</i>]Ā[1,2,4]ĀtriazoloĀ[4,3-<i>a</i>]Āpyrazines is reported as potent PDE2/PDE10 inhibitors
with drug-like properties. Selectivity for PDE2 was obtained by introducing
a linear, lipophilic moiety on the meta-position of the phenyl ring
pending from the triazole. The SAR and protein flexibility were explored
with free energy perturbation calculations. Rat pharmacokinetic data
and <i>in vivo</i> receptor occupancy data are given for
two representative compounds <b>6</b> and <b>12</b>
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