1. Imidazo[1,2-a]pyrazine diaryl ureas: inhibitors of the receptor tyrosine kinase EphB4
- Author
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James W. Darrow, Aaron Bourret, Robert Desimone, Jin-Ming Xiong, Patricia Maciejewski, Seung H. Lee, David C. Eustice, Mihaela Diana Danca, Douglas A. Pippin, David R. Brittelli, Kropf Jeffrey E, Peter Blomgren, Melissa Hill-Drzewi, Kevin S. Currie, Lisa Elkin, Steven L. Gallion, and Scott A. Mitchell
- Subjects
animal structures ,Angiogenesis ,Clinical Biochemistry ,Receptor, EphB4 ,Pharmaceutical Science ,Angiogenesis Inhibitors ,Biochemistry ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Growth factor receptor ,Cell Line, Tumor ,Drug Discovery ,Humans ,Urea ,Receptor ,Molecular Biology ,Protein Kinase Inhibitors ,biology ,Phenylurea Compounds ,Organic Chemistry ,Imidazoles ,Angiopoietin receptor ,Vascular endothelial growth factor ,chemistry ,Pyrazines ,embryonic structures ,biology.protein ,Cancer research ,Molecular Medicine ,Signal transduction ,Platelet-derived growth factor receptor - Abstract
Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent® and Nexavar®, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs.
- Published
- 2009