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.
Ibrahim
Nada
N
UMR 176 CNRS/Institut Curie, Bât. 110, Institut Curie, Centre Universitaire, 91405 Orsay, France.
Mouawad
Liliane
L
Legraverend
Michel
M
D000595:Amino Acid Sequence; D038341:Glycogen Synthase Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011687:Purines; D038341:Glycogen Synthase Kinases