Novel indolylindazolylmaleimides as inhibitors of protein kinase C-beta: synthesis, biological activity, and cardiovascular safety.
Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-beta with good to excellent selectivity vs other PKC isozymes and GSK-3beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-betaII (IC(50) = 20-25 nM). In cardiovascular safety assessment, representative lead compounds bound to the hERG channel with high affinity, potently inhibited ion current in a patch-clamp experiment, and caused a dose-dependent increase of QT(c) in guinea pigs.
Zhang
Han-Cheng
HC
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA. hzhang@prdus.jnj.com
Derian
Claudia K
CK
McComsey
David F
DF
White
Kimberly B
KB
Ye
Hong
H
Hecker
Leonard R
LR
Li
Jian
J
Addo
Michael F
MF
Croll
Diane
D
Eckardt
Annette J
AJ
Smith
Charles E
CE
Li
Quan
Q
Cheung
Wai-Man
WM
Conway
Bruce R
BR
Emanuel
Stuart
S
Demarest
Keith T
KT
Andrade-Gordon
Patricia
P
Damiano
Bruce P
BP
Maryanoff
Bruce E
BE
D000818:Animals; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D006168:Guinea Pigs; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016209:Interleukin-8 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008133:Long QT Syndrome / Q000139:chemically induced; D008301:Maleimides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D064546:Protein Kinase C beta; D013329:Structure-Activity Relationship
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007191:Indazoles; D007211:Indoles; D016209:Interleukin-8; D007527:Isoenzymes; C000606913:KCNH2 protein, human; D008301:Maleimides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3