ABSTRACT
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Subject(s)
Aminopyridines/chemical synthesis , Potassium Channels, Voltage-Gated/metabolism , Pyridines/chemical synthesis , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Biological Availability , Cell Line , Dogs , ERG1 Potassium Channel , Electrocardiography/drug effects , Ether-A-Go-Go Potassium Channels , In Vitro Techniques , Lung/enzymology , Macaca mulatta , Male , Mice , Microsomes, Liver/metabolism , Phosphorylation , Pyridines/pharmacokinetics , Pyridines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tissue Distribution , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Subject(s)
Nitriles/chemical synthesis , Nitriles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Dogs , Macaca mulatta , Molecular Structure , Nitriles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Sensitivity and Specificity , Structure-Activity Relationship , Thiazoles/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Chemical Phenomena , Chemistry, Physical , Dogs , Drug Design , Enzyme Inhibitors/pharmacokinetics , Half-Life , Hydrogen-Ion Concentration , Indicators and Reagents , Molecular Conformation , Rats , Structure-Activity RelationshipABSTRACT
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.