Abstract
Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
MeSH terms
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Animals
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Binding, Competitive
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Biological Availability
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Cell Membrane Permeability
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Class III Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Crystallography, X-Ray
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Drug Discovery
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Humans
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Isoenzymes
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Models, Molecular
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Molecular Docking Simulation
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Phosphoinositide-3 Kinase Inhibitors / pharmacokinetics*
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Phosphoinositide-3 Kinase Inhibitors / pharmacology*
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Phosphoinositide-3 Kinase Inhibitors / toxicity
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Rats
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Structure-Activity Relationship
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 III Phosphatidylinositol 3-Kinases
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PIK3CD protein, human