Abstract
The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse i.v. t(1/2) = 0.3 h, p.o. F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (i.v. t(1/2) = 5.0 h, p.o. F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Crystallography, X-Ray
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Humans
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Isoquinolines / chemistry*
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Mice
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Molecular Structure
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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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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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacology*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Isoquinolines
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Protein Kinase Inhibitors
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Pyridines
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Proto-Oncogene Proteins c-akt
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isoquinoline
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pyridine