title: Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
abstract: Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
authors.affiliation: Oncology Research, Novartis Pharma AG, Basel, Switzerland. paul.manley@pharma.novartis.com
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Guido
authors.initials: G
authors.lastname: Bold
authors.forename: Josef
authors.initials: J
authors.lastname: Brüggen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Christian R
authors.initials: CR
authors.lastname: Schnell
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.forename: Martin
authors.initials: M
authors.lastname: Haberey
authors.forename: Andreas
authors.initials: A
authors.lastname: Huth
authors.forename: Martin
authors.initials: M
authors.lastname: Krüger
authors.forename: Andreas
authors.initials: A
authors.lastname: Menrad
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ottow
authors.forename: Dieter
authors.initials: D
authors.lastname: Seidelmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Thierauch
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C470201:2-((4-pyridyl)methyl)amino-N-(3-(trifluoromethyl)phenyl)benzamide; D000577:Amides; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C470202:N-3-isoquinolinyl-2-((4-pyridinylmethyl)amino)benzamide; D062367:ortho-Aminobenzoates; D040262:Receptors, Vascular Endothelial Growth Factor