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C.J. Thut, F. Kinose, R. Breese, M. Fraley, W.F. Hoffman, K. Thomas, K. Koblan, T. Vogt; A Novel, Orally–Bioavailable KDR Kinase Inhibitor Decreases Neovascularization in Animal Models of Microvascular Disease . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1845.
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Purpose: Inhibition of the VEGF pathway has shown great promise for the treatment of ocular microvascular diseases. We have identified an orally bioavailable small molecule inhibitor of VEGFR2 (KDR) that reduces neovascularization in animal models of these diseases. Methods: Receptor specificity of the KDR kinase inhibitor was assessed using a variety of in vitro and cell culture assays. Pharmacodynamic assays in rats were performed using standard procedures. A rat laser CNV model (Brown Norway) and a mouse ROP model (C57BL/6) were used to assess the efficacy of the compound in preclinical animal models that display features of wet AMD and proliferative diabetic retinopathy. Results: Receptor binding and cell culture assays show that the KDR kinase inhibitor is a potent antagonist of KDR kinase activity on both the human and mouse receptors (IC50=7.8–19.5) and in cell–based migration assays (IC50=8 nM). Pharmacokinetic assays in the rat indicate a Cmax=470 nM and t 1/2 of 1.4 hr. In the rat laser CNV model, 12 day oral dosing of the compound immediately following laser treatment showed a statistically significant decrease in lesion size when compared to vehicle control. Five day dosing of the compound in neonatal mice that had been previously subjected to 5 days of 75% oxygen also showed a decrease in the degree of neovascularization vs. vehicle. Conclusions: We have identified an orally bioavailable, small molecule inhibitor of KDR kinase activity that can reduce neovascularization in two well–established animal models of ocular neovascular disease.
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