title: Inhibition of retinal and choroidal neovascularization by a novel KDR kinase inhibitor.
abstract: OBJECTIVE
  Inhibition of vascular endothelial growth factor (VEGF) signaling has shown great promise for the treatment of ocular neovascular disease. Current anti-VEGF therapies in late-stage development, while efficacious, require dosing by frequent intravitreal injections that are inconvenient to patients. VEGF signaling inhibitors that demonstrate more convenient dosing regimens could lead to the improved treatment of neovascular diseases such as wet age related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). Here we describe the assessment of a KDR (VEGFR2) kinase inhibitor in two well-established models of ocular neovascularization following oral administration.
  
  
  METHODS
  A novel KDR kinase inhibitor was dosed by oral gavage for 12 days at 0, 10, 30, or 100 mg/kg in an adult male Brown Norway rat laser induced choroidal neovascularization (CNV) model. The areas of CNV lesions were quantitated by fluorescence image analysis of FITC-dextran perfused animals. The kinase inhibitor was also assessed in a rat oxygen induced retinopathy (OIR) model in which neonatal rats were placed in an oxygen chamber that delivered alternating 24 h cycles of 50% and 10% oxygen for 14 days. After 14 days of oxygen treatment, the animals were returned to room air and dosed orally for 7 days with 0, 10, or 30 mg/kg kinase inhibitor. The extent of retinal neovascularization was assessed by counting pre-retinal neovascular nuclei on histological sections.
  
  
  RESULTS
  At doses of 100 mg/kg, the KDR kinase inhibitor resulted in a 98% reduction in lesion size in the rat CNV model. 30 mg/kg doses of the inhibitor showed a 70% and 80% reduction in lesion size in the laser CNV and OIR models, respectively.
  
  
  CONCLUSIONS
  Oral dosing of the described KDR kinase inhibitor effectively inhibits neovascularization in two well-established animal models of ocular neovascularization. These data suggest that compounds of this class may prove to be useful for the treatment of a variety of ocular neovascular diseases using a convenient oral dosing regimen.
authors.affiliation: Department of Ophthalmics Research, Merck & Co., West Point, PA 19486, USA.
authors.forename: Fumi
authors.initials: F
authors.lastname: Kinose
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Roscilli
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamartina
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Anderson
authors.forename: Fabio
authors.initials: F
authors.lastname: Bonelli
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Spence
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Holder
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Thut
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000201:enzymology / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis; D005451:Fluorescein Angiography; D007211:Indoles / Q000008:administration & dosage* / Q000138:chemical synthesis; D053685:Laser Therapy; D008297:Male; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000633:toxicity; D015363:Quinolones / Q000008:administration & dosage* / Q000138:chemical synthesis; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000175:diagnosis / Q000201:enzymology / Q000517:prevention & control*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: C509383:3-(5-(2-((2-methoxyethyl)(methyl)amino)ethoxy)-1H-indol-2-yl)-2(1H)-quinolinone; D004791:Enzyme Inhibitors; D007211:Indoles; D015363:Quinolones; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen