3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3.
A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3beta and selectivity versus PKC-betaII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3beta (IC(50)=7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-betaII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3beta.
Zhang
Han-Cheng
HC
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. hzhang@prdus.jnj.com
Ye
Hong
H
Conway
Bruce R
BR
Derian
Claudia K
CK
Addo
Michael F
MF
Kuo
Gee-Hong
GH
Hecker
Leonard R
LR
Croll
Diane R
DR
Li
Jian
J
Westover
Lori
L
Xu
Jun Z
JZ
Look
Richard
R
Demarest
Keith T
KT
Andrade-Gordon
Patricia
P
Damiano
Bruce P
BP
Maryanoff
Bruce E
BE
D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008301:Maleimides / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D008301:Maleimides; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3