Abstract
Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.
MeSH terms
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Animals
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Asthma / chemically induced
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Asthma / drug therapy*
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Class Ib Phosphatidylinositol 3-Kinase / metabolism*
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Crystallography, X-Ray
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Humans
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Leukocytes, Mononuclear / drug effects
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Male
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Molecular Structure
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Ovalbumin
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Rats
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Rats, Inbred BN
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / metabolism
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Sulfonamides / pharmacokinetics
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Sulfonamides / therapeutic use*
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Thiazoles / chemical synthesis
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Thiazoles / metabolism
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Thiazoles / pharmacokinetics
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Thiazoles / therapeutic use*
Substances
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Protein Kinase Inhibitors
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Sulfonamides
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Thiazoles
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Ovalbumin
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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
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Pik3cd protein, rat