Abstract
A series of substituted 3-aryl-6-amino-triazolo[4,3-b]pyridazines were identified as highly selective inhibitors of Pim-1 kinase. Initial exploration identified compound 24 as a potent, selective inhibitor, limited in its utility by poor solubility and permeability. Understanding the unusual ATP-binding site of the Pim kinases and X-ray crystallographic data on compound 24 led to design improvements in this class of inhibitor. This resulted in compound 29, a selective, soluble and permeable inhibitor of Pim-1.
MeSH terms
-
Animals
-
Cell Line
-
Crystallography, X-Ray
-
Dogs
-
Drug Design
-
Permeability
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacology
-
Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-pim-1 / metabolism
-
Pyridazines / chemical synthesis
-
Pyridazines / chemistry*
-
Pyridazines / pharmacology
-
Solubility
-
Structure-Activity Relationship
-
Triazoles / chemical synthesis
-
Triazoles / chemistry*
-
Triazoles / pharmacology
Substances
-
Protein Kinase Inhibitors
-
Pyridazines
-
Triazoles
-
Proto-Oncogene Proteins c-pim-1