May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
AGN–199659, a Novel Tyrosine Kinase Inhibitor, Blocks Choroidal Neovascularization in the Rat.
Author Affiliations & Notes
  • G.W. De Vries
    Biological Sciences,
    Allergan Inc, Irvine, CA
  • J. Edelman
    Biological Sciences,
    Allergan Inc, Irvine, CA
  • A. McLaughlin
    Biological Sciences,
    Allergan Inc, Irvine, CA
  • G. Rodrigues
    Biological Sciences,
    Allergan Inc, Irvine, CA
  • J. Shen
    Pharmacokinetics,
    Allergan Inc, Irvine, CA
  • J. Wurster
    Chemical Sciences,
    Allergan Inc, Irvine, CA
  • T. Malone
    Chemical Sciences,
    Allergan Inc, Irvine, CA
  • S. Andrews
    Array BioPharma, Boulder, CO
  • Footnotes
    Commercial Relationships  G.W. De Vries, Allergan, Inc. E; J. Edelman, Allergan, Inc. E; A. McLaughlin, Allergan, Inc. E; G. Rodrigues, Allergan, Inc. E; J. Shen, Allergan, Inc. E; J. Wurster, Allergan, Inc. E; T. Malone, Allergan, Inc. E; S. Andrews, Array BioPharma E.
  • Footnotes
    Support  none
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 480. doi:
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      G.W. De Vries, J. Edelman, A. McLaughlin, G. Rodrigues, J. Shen, J. Wurster, T. Malone, S. Andrews; AGN–199659, a Novel Tyrosine Kinase Inhibitor, Blocks Choroidal Neovascularization in the Rat. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):480.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: There is evidence suggesting that VEGF and PDGF play key roles in the development of angiogenesis both in tumors and in retinal disease. We examined the effect of AGN–199659, a novel tyrosine kinase inhibitor which blocks activation of both VEGF and PDGF receptors, on laser–induced choroidal neovascularization (CNV) in the rat. Methods: Adult Brown Norway rats were dosed orally with AGN–199659 (3–[(4–morpholin–4–yl–phenylamino)–methylene]–1,3–dihydro–indol–2–one) at 5–75 mg/kg/day in PEG 400 vehicle for 10 days. CNV was induced using an Argon laser at a power setting of 90 mW for 100 ms and a spot diameter of 100 microns. CNV was visualized with FITC dextran in RPE–choroid–sclera flat mounts at day 10 following laser injury. Quantification of lesion size was done with image capture and analysis software. Serial blood samples were collected following drug treatment, and plasma concentration of AGN–199659 was determined using an LC/MS/MS method. Results: Three days after laser–injury in vehicle treated animals approximately 50% of the lesions showed FITC–dextran labeling indicative of CNV. By day 10, all lesions were vascularized and the maximal area was attained. Treatment with AGN–199659 produced a dose–dependent (ID50 20 mg/kg/day) inhibition of CNV formation at day 10, with the highest dose inhibiting approximately 95%. Maximum inhibition occurred when total drug plasma concentrations were maintained above approximately 250 nM. These are the same concentrations required to inhibit VEGF and PDGF receptor activation in vitro (IC50 values of 250 nM and 950 nM, respectively). Conclusions: These data are consistent with the hypothesis that VEGF and PDGF signaling pathways are important regulators of choroidal neovascularization and that tyrosine kinase inhibitors with pharmacological profiles similar to AGN–199659 may be useful in treating retinal diseases characterized by CNV.

Keywords: choroid: neovascularization • growth factors/growth factor receptors • pharmacology 
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