Novel 8-arylated purines as inhibitors of glycogen synthase kinase

A series of 8-arylated purine derivatives bearing either an aniline or an alkyl amide at position 6 were found to inhibit glycogen synthase kinase-3, with good selectivity over ten kinases. Molecular modeling studies indicated that the most active compounds (8a and 8e), adopt a planar conformation, close to the shape of AMPPNP in the crystal structure of GSK-3. These compounds are stabilized by hydrophobic contacts between the 8-aromatic group and the protein adenine pocket and by electrostatic contacts.

The synthesis of a library of 8-arylated-6-substituted purines allowed the identification of inhibitors of Glycogen Synthase Kinase (GSK-3) which were docked in the ATP binding site of the kinase.Figure optionsDownload as PowerPoint slide