Abstract
We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.
MeSH terms
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Animals
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy*
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Collagen
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Disease Models, Animal
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Dogs
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Dose-Response Relationship, Drug
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Drug Discovery*
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Female
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / blood
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Intracellular Signaling Peptides and Proteins / metabolism
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Liver / drug effects
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Molecular Conformation
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / blood
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Protein-Tyrosine Kinases / metabolism
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Rats
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Rats, Inbred Lew
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Structure-Activity Relationship
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Syk Kinase
Substances
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Collagen
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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Syk protein, rat
Associated data
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PDB/4RX7
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PDB/4RX8
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PDB/4RX9