5-aryl-pyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
Witherington
Jason
J
Department of Medicinal Chemistry, Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline Research Limited, New Frontiers Science Park, Third Avenue, Essex CM19 5AW, Harlow, UK. jason_witherington@gsk.com
Bordas
Vincent
V
Haigh
David
D
Hickey
Deirdre M B
DM
Ife
Robert J
RJ
Rawlings
Anthony D
AD
Slingsby
Brian P
BP
Smith
David G
DG
Ward
Robert W
RW
D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D011720:Pyrazoles; D011724:Pyridazines; D038362:Glycogen Synthase Kinase 3