Abstract
A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homology model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the observed selectivity over CDK2. An X-ray crystal structure of a compound from the active series bound to crystalline MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives showing good in vitro cellular potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line
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Crystallography, X-Ray
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HSP27 Heat-Shock Proteins / metabolism
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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 / chemistry
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Phosphorylation
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Protein Conformation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Shock, Septic / metabolism
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Small Molecule Libraries
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Stereoisomerism
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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HSP27 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Pyrazoles
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Pyrimidines
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Small Molecule Libraries
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Tumor Necrosis Factor-alpha
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases