ABSTRACT
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Indoles/chemical synthesis , Indoles/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Biological Availability , Cell Line , Half-Life , Indoles/pharmacology , Inhibitory Concentration 50 , Rats , Structure-Activity RelationshipABSTRACT
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.