Abstract
Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Arthritis, Rheumatoid / drug therapy*
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Crystallography, X-Ray
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Humans
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Quinoxalines / chemistry
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Quinoxalines / pharmacology*
Substances
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Protein Kinase Inhibitors
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Quinoxalines
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human