Abstract
In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.
MeSH terms
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Adenosine Triphosphate / metabolism
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Administration, Oral
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Animals
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Binding Sites
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Humans
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Isoenzymes
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Leukocyte Disorders / chemically induced
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Leukocyte Disorders / drug therapy
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Lipopolysaccharides / toxicity
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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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Phthalimides / chemistry
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Rats
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Isoenzymes
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Lipopolysaccharides
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Phosphoinositide-3 Kinase Inhibitors
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Phthalimides
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phthalimidine
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Adenosine Triphosphate