Aya Shoda

6-(4-Pyridyl)pyrimidin-4(3H)-ones as CNS penetrant glycogen synthase kinase-3β inhibitors.

The discovery of a series of 6-(4-pyridyl)pyrimidin-4(3H)-ones derived from a hit compound with low molecular weight and sufficient chemical space is reported. Transformation of substituents led to subnanomolar potent inhibitors with in vivo tau phoshorylation lowering activity.

2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; A new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors

A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.