ABSTRACT
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
Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.