Studies with an Orally Bioavailable α_V Integrin Antagonist in Animal Models of Ocular Vasculopathy: Retinal Neovascularization in Mice and Retinal Vascular Permeability in Diabetic Rats

Abstract

The ␣ V integrins are key receptors involved in mediating cell migration and angiogenesis. In age-related macular degeneration (AMD) and diabetic retinopathy, angiogenesis plays a critical role in the loss of vision. These ocular vasculopathies might be treatable with a suitable ␣ V antagonist, and an oral drug would offer a distinct advantage over current therapies. (3,S,␤,S)-1,2,3,4-Tetrahydro-␤- [[1-[1-oxo-3-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-quinolinepropanoic acid (JNJ-26076713) is a potent, orally bioavailable, nonpeptide ␣ V antagonist derived from the arginine-glycine-asparagine binding motif in the matrix protein ligands (e.g., vitronectin). This compound inhibits ␣ V ␤ 3 and ␣ V ␤ 5 binding to vitronectin in the low nanomolar range, it has excellent selectivity over integrins ␣ IIb ␤ 3 and ␣ 5 ␤ 1 , and it prevents adhesion to human, rat, and mouse endothelial cells. JNJ-26076713 blocks cell migration induced by vascular endothelial growth factor, fibroblast growth factor (FGF), and serum, and angiogenesis induced by FGF in the chick chorioallantoic membrane model. JNJ-26076713 is the first ␣ V antagonist reported to inhibit retinal neovascularization in an oxygen-induced model of retinopathy of prematurity after oral administration. In diabetic rats, orally administered JNJ-26076713 markedly inhibits retinal vascular permeability, a key early event in diabetic macular edema and AMD. Given this profile, JNJ-26076713 represents a potential therapeutic candidate for the treatment of age-related macular degeneration, macular edema, and proliferative diabetic retinopathy.Age-related macular degeneration (AMD) is the leading cause of blindness in people over 55 years of age, and diabetic retinopathy (DR) in people under 55 years of age (Klein et al., 1994;Williams et al., 2004). Both disease conditions are characterized by new blood vessel growth-choroidal neovascularization in AMD and retinal neovascularization in DR (Freund, 1993;Speicher et al., 2003;Williams et al., 2004;Zarbin, 2004). There is ample evidence that ␣ V integrins are involved in ocular angiogenesis. Proangiogenic growth factors, including VEGF and FGF, are up-regulated in AMD and DR and they stimulate ␣ V expression. In the well established mouse model of oxygen-induced retinopathy (OIR), or retinopathy of prematurity (ROP) model, ␣ V integrins and the Article, publication date, and citation information can be found at

Importance of integrin receptors in the field of pharmaceutical & medical science

“…Another antagonist of αv integrins, JNJ-26076713 (a small molecule type antagonist) that is orally available, is worth mentioning here. This antagonist was also found to be very effective in the prevention of retinal neovascularization in mice model of ROP [92].…”

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

“…These findings can potentially explain the different time-windows that are used to perform the retinal vascular leakage read-out in the diabetic rat STZ model. Some research groups already assess the permeability level in the diabetic rat eyes approximately 2 weeks after STZ injection [70,73,75,104], while most groups determine the increased leakage level after a longer period of hyperglycemia even up to 6 months postinjection [61, 69,96,105,106].…”

“…rat VEGFinduced retinal permeability model [71,107], the quantitative Evans Blue method is also often applied in the diabetic rodent STZ model [71,98,104]. Several studies have demonstrated that perfusion with FITC-conjugated albumin or dextran in STZ-induced diabetic animals is a reliable technique to assess retinal permeability quantitatively [69,106,108,109] (Figure 1).…”

Dynamic interactions between cells and their extracellular matrix mediate embryonic development

“…Recent experiments elucidating the extracellular ''interactome'' of the FGF receptor-ligand system have shown that ECM receptors act as noncanonical co-receptors that impart specificity to FGF signaling (Polanska et al, 2008). For example, inhibition of alpha V integrin can block FGF induced cell adhesion, migration, and angiogenesis (Rusnati et al, 1997;Santulli et al, 2008). This type of regulation provides mechanistic insight into how crosstalk between cell adhesion receptors and signaling pathways mediates cellular behavior.…”