title: A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis.
abstract: 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.
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Bold
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: McSheehy
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Josef
authors.initials: J
authors.lastname: Brüggen
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Drückes
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Burglin
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Dürler
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Loretan
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Reuter
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Theuer
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bauer-Probst
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Martiny-Baron
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Allegrini
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Goepfert
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Amanda
authors.initials: A
authors.lastname: Littlewood-Evans
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2