Abstract
Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
MeSH terms
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Aminopyridines / chemical synthesis
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Aminopyridines / pharmacokinetics
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Aminopyridines / therapeutic use*
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Aminopyridines / toxicity
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / therapeutic use*
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Anti-Inflammatory Agents / toxicity
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Class Ib Phosphatidylinositol 3-Kinase / metabolism*
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Female
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Humans
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Inflammation / drug therapy*
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Molecular Structure
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No-Observed-Adverse-Effect Level
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Protein Kinase Inhibitors / toxicity
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Pyrazines / chemical synthesis
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Pyrazines / pharmacokinetics
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Pyrazines / therapeutic use
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Pyrazines / toxicity
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Aminopyridines
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Anti-Inflammatory Agents
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Protein Kinase Inhibitors
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Pyrazines
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Class Ib Phosphatidylinositol 3-Kinase
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Pik3cg protein, rat