Abstract
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
MeSH terms
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Animals
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B-Lymphocytes / drug effects
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B-Lymphocytes / enzymology
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Blood Proteins / metabolism
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Crystallography, X-Ray
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Protein Binding
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacology
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Pyrazines / toxicity
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacology
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Pyrroles / toxicity
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Structure-Activity Relationship
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Syk Kinase
Substances
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Blood Proteins
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Intracellular Signaling Peptides and Proteins
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Pyrazines
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Pyrroles
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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