Abstract
The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Caco-2 Cells
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Crystallography, X-Ray
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Cyclopropanes / chemical synthesis*
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Cyclopropanes / pharmacokinetics
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Cyclopropanes / pharmacology
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Gene Knockdown Techniques
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High-Throughput Screening Assays
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Humans
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Interleukin-2 / physiology
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Janus Kinase 1 / antagonists & inhibitors*
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Janus Kinase 1 / genetics
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Janus Kinase 1 / metabolism
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Janus Kinase 3 / antagonists & inhibitors*
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Janus Kinase 3 / genetics
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Janus Kinase 3 / metabolism
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Mice
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Models, Molecular
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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RNA, Small Interfering / genetics
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Rats
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Receptors, Interleukin-6 / physiology
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Signal Transduction / drug effects
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Structure-Activity Relationship
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclopropanes
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Interleukin-2
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Pyrazines
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Pyrroles
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RNA, Small Interfering
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Receptors, Interleukin-6
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Janus Kinase 1
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Janus Kinase 3