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N. Patel, L. Adams, C. Sun, D. Moshinsky, X. Wang, K. Leahy, K.G. Moss, S. Yamazaki, M. Shawer, A. Howlett; A Selective Inhibitor of VEGFR Inhibits Angiogenesis and Vascular Permeability: In vitro and In vivo Evidence . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2903.
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Purpose: Vascular epithelial growth factor (VEGF) is a key driver of angiogenesis and vascular permeability underlying the loss of visual acuity in diabetic retinopathy and neovascular age-related macular degeneration. We identified a small molecule kinase inhibitor of VEGFR, SU10944, that inhibits neovascularization and permeability, and is distributed to the eye upon systemic delivery. Methods: SU10944 was characterized in a series of biochemical and cell based assays for selectivity against VEGFR. Additionally, SU10944 was tested in two in vivo efficacy models, the rat VEGF-stimulated corneal micropocket model of angiogenesis and the mouse Miles assay for inhibition of vascular permeability. Lastly, the pharmacokinetic parameters and drug concentration in the eye globe were determined in rat following a single intravenous dose. Results: In biochemical assays, SU10944 exhibited an IC50 of approximately 0.07 uM against VEGFR2, 1.4 uM for FGF-R1, >20 uM for Src, and >100 uM for EGFR. Similar to the biochemical results, SU10944 was selective for VEGFR in cellular assays with IC50 values of 0.1-0.2 uM for VEGFR, 2.4 uM for FGFR, and >50 for EGFR. In the corneal micropocket assay, SU10944 gave a clear dose response with an ED50 for inhibition of neovascularization of approximately 30 mpk and a maximum inhibition of 95% at 300 mpk. In the Miles assay, SU10944 inhibited VEGF-induced vascular permeability: plasma exposures of approx. 0.6 ug/ml were associated with 50% inhibition. Additionally, rat pharmacokinetic data showed SU10944-related radioactivity distributed to the eye globe, and that clearance kinetics in the eye mimicked plasma kinetics with an apparent terminal half-life of about 6 hours. The eye-to-plasma drug concentration ratio was approximately 0.06. Conclusions: We identified a small molecule selective kinase inhibitor of VEGFR that inhibits both angiogenesis and vascular permeability. Upon systemic delivery, the compound can be detected in the eye. Further studies are planned to determine the time-concentration distribution to specific ocular tissues.
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