Abstract
A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.
MeSH terms
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Cell Line
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Drug Discovery*
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Humans
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Hydrophobic and Hydrophilic Interactions
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Models, Molecular
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Piperidines / chemistry*
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Piperidines / metabolism
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Piperidines / pharmacology*
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Protein Conformation
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Substrate Specificity
Substances
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Enzyme Inhibitors
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Isoenzymes
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Phosphoinositide-3 Kinase Inhibitors
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Piperidines
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piperidine