Abstract
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
MeSH terms
-
Crystallography, X-Ray
-
Humans
-
Models, Molecular
-
Molecular Structure
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Pyrazoles / chemistry*
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology*
-
Structure-Activity Relationship
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
p38 Mitogen-Activated Protein Kinases / chemistry
-
p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrimidines
-
p38 Mitogen-Activated Protein Kinases
-
pyrimidine