ABSTRACT
The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Inbred NOD , Mice, SCID , Models, Molecular , Protein Kinase Inhibitors/pharmacokinetics , Quinolones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
3-Benzimidazol-2-yl-1H-indazole analogs were developed as inhibitors of receptor tyrosine kinases (RTK). The synthesis and SAR of this series is reported.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Indazoles/chemistry , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Herein are described a series of novel heterocyclic analogs of the 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one scaffold. These compounds are potent inhibitors of receptor tyrosine kinases and exhibit favorable pharmacokinetic profiles. The synthesis and SAR of these compounds are described.