Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β.

Reperfusion-induced temporary appearance of therapeutic window in penumbra after 2 h of photothrombotic middle cerebral artery occlusion in rats.

To explore the effects of reperfusion on evolution of focal ischemic injury, spontaneously hypertensive male rats were subjected to photothrombotic distal middle cerebral artery occlusion (MCAO) with or without YAG laser-induced reperfusion. The volume of fodrin breakdown zone, water content, and brain tissue levels of sodium (Na(+)) and potassium (K(+)) were measured in the ischemic core and penumbra. Reperfusion attenuated fodrin breakdown, and the volume containing fodrin breakdown product at 3 h after reperfusion (5 h after MCAO) (30+/-7 mm(3)) was significantly smaller than the 42+/-3 mm(3) of the permanent occlusion group.

Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease.

Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival.