Abstract
A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Dose-Response Relationship, Drug
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Interferon-gamma / biosynthesis
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Interleukin-2 / antagonists & inhibitors
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Janus Kinase 3 / antagonists & inhibitors*
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Mice
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Models, Animal
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Models, Molecular
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Molecular Structure
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Purines / chemical synthesis
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Purines / chemistry
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Purines / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Benzimidazoles
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Enzyme Inhibitors
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Interleukin-2
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Purines
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Interferon-gamma
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Janus Kinase 3