Abstract
A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.
MeSH terms
-
Binding Sites
-
Computer-Aided Design
-
Drug Design*
-
Enzyme Inhibitors / blood
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Humans
-
Inhibitory Concentration 50
-
Molecular Structure
-
Structure-Activity Relationship
-
Triazoles / blood
-
Triazoles / chemical synthesis*
-
Triazoles / chemistry
-
Triazoles / pharmacology*
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Substances
-
Enzyme Inhibitors
-
Triazoles
-
p38 Mitogen-Activated Protein Kinases