Abstract
We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110alpha inhibitor; however, although 4 is a potent inhibitor of p110alpha enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo. To increase stability the pyrazole of 4 was replaced with a hydrazone and a moderately potent p110alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110alpha inhibitors, including 8c and 8h, with IC(50) values of 0.30 nM and 0.26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects
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Humans
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Hydrazones / chemistry*
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Imidazoles / chemistry
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Inhibitory Concentration 50
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Mice
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Molecular Structure
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / 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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Sulfur / chemistry*
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Temperature
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Xenograft Model Antitumor Assays
Substances
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Hydrazones
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Imidazoles
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Isoenzymes
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Protein Subunits
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Pyridines
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Sulfur
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imidazole
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pyridine