Abstract
Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.
MeSH terms
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Amides / chemical synthesis
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Amides / pharmacology
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Animals
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Computational Biology
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Computer Simulation
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Drug Design
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Ether-A-Go-Go Potassium Channels / drug effects
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Humans
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In Vitro Techniques
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Conformation
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Mutagenesis / drug effects
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Mutagenicity Tests
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacokinetics
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Pyridazines / pharmacology*
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Rats
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Spleen / drug effects
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Spleen / enzymology*
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Structure-Activity Relationship
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X-Ray Diffraction
Substances
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Amides
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Ether-A-Go-Go Potassium Channels
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KCNH1 protein, human
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Protein Kinase Inhibitors
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Pyridazines
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Protein-Tyrosine Kinases