Abstract
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Aminopyridines / chemical synthesis
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Aminopyridines / chemistry*
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Aminopyridines / pharmacokinetics
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Animals
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Cell Line, Tumor
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Cytochrome P-450 Enzyme System / metabolism*
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Dogs
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Haplorhini
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Humans
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Mice
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Phosphorylation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / pharmacokinetics
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Pyridines / chemistry*
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Rats
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Aminopyridines
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Protein Kinase Inhibitors
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Pyrazines
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Pyridines
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Cytochrome P-450 Enzyme System
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Gsk3b protein, rat
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3