Document Report Card

ID: ALA1142718

Journal: J Med Chem

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

Authors: 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.

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.

CiteXplore: 15771419

DOI: 10.1021/jm049478u