Abstract
An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
MeSH terms
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Animals
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / enzymology
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Class I Phosphatidylinositol 3-Kinases / metabolism*
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Class Ib Phosphatidylinositol 3-Kinase / metabolism*
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Drug Discovery / methods*
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Female
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Humans
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Isoenzymes
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Mice
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Molecular Docking Simulation
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PC-3 Cells
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Phosphoinositide-3 Kinase Inhibitors / chemical synthesis*
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Phosphoinositide-3 Kinase Inhibitors / chemistry
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Phosphoinositide-3 Kinase Inhibitors / pharmacokinetics
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Phosphoinositide-3 Kinase Inhibitors / pharmacology
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RAW 264.7 Cells
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Rats, Sprague-Dawley
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Rats, Wistar
Substances
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Isoenzymes
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Phosphoinositide-3 Kinase Inhibitors
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Class I Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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PIK3CD protein, human
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PIK3CG protein, human