Abstract
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
MeSH terms
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / pharmacology
-
Humans
-
Lipopolysaccharides / pharmacology
-
Pyrazoles / chemical synthesis*
-
Pyrazoles / pharmacology
-
Structure-Activity Relationship
-
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
-
Tumor Necrosis Factor-alpha / biosynthesis
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
p38 Mitogen-Activated Protein Kinases / chemistry
Substances
-
Enzyme Inhibitors
-
Lipopolysaccharides
-
Pyrazoles
-
Tumor Necrosis Factor-alpha
-
p38 Mitogen-Activated Protein Kinases