Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
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.
Manley
Paul W
PW
Oncology Research, Novartis Pharma AG, Basel, Switzerland. paul.manley@pharma.novartis.com
Furet
Pascal
P
Bold
Guido
G
Brüggen
Josef
J
Mestan
Jürgen
J
Meyer
Thomas
T
Schnell
Christian R
CR
Wood
Jeanette
J
Haberey
Martin
M
Huth
Andreas
A
Krüger
Martin
M
Menrad
Andreas
A
Ottow
Eckhard
E
Seidelmann
Dieter
D
Siemeister
Gerhard
G
Thierauch
Karl-Heinz
KH
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
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