Abstract
A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Binding Sites
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Cell Line
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Computer Simulation
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Crystallography, X-Ray
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Humans
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Interleukin-8 / blood
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Lipopolysaccharides / pharmacology
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Male
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 14 / metabolism
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Pyrazoles / administration & dosage
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Pyrazoles / chemistry*
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Pyrazoles / pharmacokinetics
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Pyridones / administration & dosage
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Pyridones / chemistry*
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Pyridones / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Interleukin-8
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Lipopolysaccharides
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridones
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Tumor Necrosis Factor-alpha
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Mitogen-Activated Protein Kinase 14