Abstract
The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Arthritis / chemically induced
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Arthritis / drug therapy
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Binding Sites
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Collagen / adverse effects
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Dogs
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Drug Discovery*
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Female
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Ligands
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Male
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Mice
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Models, Molecular
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Protein Conformation
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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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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / metabolism
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Rats
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology*
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Small Molecule Libraries / therapeutic use
Substances
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Ligands
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Protein Kinase Inhibitors
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Small Molecule Libraries
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Adenosine Triphosphate
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Collagen
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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Btk protein, mouse