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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 (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 QTc in guinea pigs.
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Reference£º
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem