A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis

• Published in: Journal of medicinal chemistry Vol. 59; no. 1; pp. 132 - 146
• Main Authors: Bold, Guido, Schnell, Christian, Furet, Pascal, McSheehy, Paul, Brüggen, Josef, Mestan, Jürgen, Manley, Paul W, Drückes, Peter, Burglin, Marion, Dürler, Ursula, Loretan, Jacqueline, Reuter, Robert, Wartmann, Markus, Theuer, Andreas, Bauer-Probst, Beatrice, Martiny-Baron, Georg, Allegrini, Peter, Goepfert, Arnaud, Wood, Jeanette, Littlewood-Evans, Amanda
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.01.2016; Amer Chemical Soc
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Animals; Cell Proliferation - drug effects; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; Female; Human Umbilical Vein Endothelial Cells; Humans; Life Sciences & Biomedicine; Melanoma, Experimental - drug therapy; Mice; Models, Molecular; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Pharmacology & Pharmacy; Phosphorylation; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Xenograft Model Antitumor Assays; TARGET; CELLS; THERAPY; PATHWAY; THYROID-CANCER; IN-VIVO; DISEASE; TYROSINE KINASE INHIBITOR; MECHANISMS; RECEPTORS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01582

This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.