Discovery of novel 2-(3-phenylpiperazin-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 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3ß. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.

Asymmetric synthesis of 2-arylpiperazines.

An asymmetric synthesis of 2-arylpiperazines starting from phenacyl bromides, a variety of which are easily available, has been established. The synthesis features a CBS reduction of phenacyl bromide to provide optically enriched compounds, an SN2 reaction of 1,2,3-oxathiazolidine 2-oxides with an azide anion with invert of configuration, and construction of the piperazine ring via reduction of piperazine-2,3-diones.

2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; a new class of potent, selective and orally active glycogen synthase kinase-3ß 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-3ß (GSK-3ß). We found 21, 29 and 30 to possess potent in vitro GSK-3ß inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.

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

The Effect of a Para Substituent on the Conformational Preference of 2,2-Diphenyl-1,3-dioxanes: Evidence for the Anomeric Effect from X-ray Crystal Structure Analysis(1).

The molecular structures of 2,2-di(para-substituted phenyl)-1,3-dioxanes were elucidated for the first time by X-ray crystallographic analysis, which revealed two important structural features: (1) These compounds have the chair conformation in which electron-withdrawing aryl groups [viz. p-nitro- or p-(trifluormethyl)phenyl] are always axial and electron-donating aryl groups (viz. p-methoxyphenyl) are always equatorial. (2) In these compounds as well as in symmetrically substituted 2,2-diphenyl-1,3-dioxane the axial C(2)-aryl bond is longer than the equatorial C(2)-aryl bond. The axial preference of the electron-withdrawing aryl group was also demonstrated in solution by (1)H and (13)C NMR spectroscopy. The anomeric carbon substituted with an electron-withdrawing aryl group resonates at an unusually high field, as does the aromatic carbon bearing the electron-withdrawing substituent. The observed (13)C NMR data clearly indicate enhanced electron density at these carbons due to the anomeric effect. Semiempirical molecular orbital calculations by the MOPAK PM3 method reproduced the bond lengthening for axial C(2)-aryl, while the heat of formation derived from this calculation failed to support the axial preference of electron-withdrawing aryl groups. The X-ray crystallographic data on the conformational preference and bond lengths at the anomeric carbon, as well as the solution NMR spectroscopic data, clearly indicate the anomeric effect that is best rationalized in terms of stabilizing interaction between the lone-pair electrons on the ring oxygens and the antibonding orbital of the axial C(2)-aryl bond.