Novel indolylindazolylmaleimides as inhibitors of protein kinase C-β:: Synthesis, biological activity, and cardiovascular safety

被引：68

作者：

Zhang, HC

Derian, CK

McComsey, DF

White, KB

Ye, H

Hecker, LR

Li, J

Addo, MF

Croll, D

Eckardt, AJ

Smith, CE

Li, Q

Cheung, WM

Conway, BR

Emanuel, S

Demarest, KT

Andrade-Gordon, P

Damiano, BP

Maryanoff, BE ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev, Drug Discovery, Spring House, PA 19477 USA

[2] Johnson & Johnson Pharmaceut Res & Dev, Drug Discovery, Raritan, NJ 08869 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 06期

关键词：

D O I：

10.1021/jm049478u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-3 beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-beta II (IC50 = 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.

引用

页码：1725 / 1728

页数：4

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