Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors.
A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar(1)) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range.
Peat
Andrew J
AJ
GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Boucheron
Joyce A
JA
Dickerson
Scott H
SH
Garrido
Dulce
D
Mills
Wendy
W
Peckham
Jennifer
J
Preugschat
Frank
F
Smalley
Terrence
T
Schweiker
Stephanie L
SL
Wilson
Jayme R
JR
Wang
Tony Y
TY
Zhou
Huiqiang Q
HQ
Thomson
Stephen A
SA
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D038362:Glycogen Synthase Kinase 3