Synthesis and evaluation of novel heterocyclic inhibitors of GSK-3.
A set of novel heterocyclic pyrimidyl hydrazones has been synthesized as inhibitors of glycogen synthase kinase-3 (GSK-3) with the most active exhibiting low nanomolar activity. Quantum mechanical calculations indicate that of the conformational factors that could determine binding affinity, the planarity of the phenyl ring in relation to the central core and the conformation of the hydrazone chain may be the most influential.
Smalley
Terrence L
TL
Research & Development, GlaxoSmithKline, Inc., 5 Moore Drive, Research Triangle Park, NC 27709, USA. terry.l.smalley@gsk.com
Peat
Andrew J
AJ
Boucheron
Joyce A
JA
Dickerson
Scott
S
Garrido
Dulce
D
Preugschat
Frank
F
Schweiker
Stephanie L
SL
Thomson
Stephen A
SA
Wang
Tony Y
TY
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006834:Hydrazines / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D006834:Hydrazines; D038362:Glycogen Synthase Kinase 3