Novel indolylindazolylmaleimides as inhibitors of protein kinase C-beta: synthesis, biological activity, and cardiovascular safety.

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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

Novel indolylindazolylmaleimides as inhibitors of protein kinase C-beta: synthesis, biological activity, and cardiovascular safety.

J Med Chem. 2005 Mar 24;48(6):1725-8.

PubMed ID

15771419 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Terfenadine	Potassium voltage-gated channel subfamily H member 2	Ki (nM)	320	N/A	N/A	Details