Fluorescent indicator displacement assay for the discovery of UGGAA repeat-targeted small molecules.

We report that a selective fluorescent indicator NBD-NCD for UGGAA repeats resulted in fluorescence quenching upon binding to RNA and recovered the fluorescence by displacing NBD-NCD with UGGAA repeat-targeted small molecules. The fluorescent indicator displacement assay using NBD-NCD can detect the interaction of small molecules with UGGAA repeats.

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3ß inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.