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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 14, 2007; DOI: 10.1124/jpet.107.131656

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Received for publication September 26, 2007.
Revised December 12, 2007.
Accepted for publication December 13, 2007.

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

Rosemary J Santulli 1*, William A Kinney 1, Shyamali Ghosh 1, Bart L DeCorte 1, Li Liu 1, Robert Tuman 1, Zhao Zhou 1, Norman Huebert 1, Sven E Bursell 2, Clermont C Alan 2, Maria B Grant 3, Lynn C Shaw 3, Shaker A Mousa 4, Robert A Galemmo 5, Dana L Johnson 1, Bruce E Maryanoff 1, Bruce P Damiano 1

1 Johnson & Johnson Pharmaceutical Research & Development 2 Beetham Eye Institute, Joslin Diabetes Center 3 University of Florida 4 Pharmaceutical Research Institute at Albany College of Pharmacy 5 Neuromed Pharmaceuticals

* Address correspondence to: E-mail: rsantull{at}prdus.jnj.com

Abstract

The {alpha}V integrins are key receptors involved in mediating cell migration and angiogenesis. In age-related macular degeneration (AMD) and diabetic retinopathy (DR), angiogenesis plays a critical role in the loss of vision. These ocular vasculopathies might be treatable with a suitable {alpha}V antagonist, and an oral drug would offer a distinct advantage over current therapies. JNJ-26076713 is a potent, orally bioavailable, nonpeptide {alpha}V antagonist derived from the arginine-glycine-asparagine (RGD) binding motif in the matrix protein ligands (e.g., vitronectin). This compound inhibits {alpha}V{beta}3 and {alpha}V{beta}5 binding to vitronectin in the low nanomolar range, has excellent selectivity over integrins {alpha}IIb{beta}3 and {alpha}5{beta}1, and prevents adhesion to human, rat, and mouse endothelial cells. JNJ-26076713 blocks cell migration induced by VEGF, FGF, and serum, as well as angiogenesis induced by FGF in the chick chorioallantoic membrane (CAM) model. JNJ-26076713 is the first {alpha}V antagonist reported to inhibit retinal neovascularization in an oxygen-induced model of retinopathy of prematurity (OIR) following 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.


Key words: VEGF, age related macular degeneration, angiogenesis, integrin, permeability, retinopathy


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 Arch OphthalmolHome page
D. Navaratna, J. Maestas, P. G. McGuire, and A. Das
Suppression of Retinal Neovascularization With an Antagonist to Vascular Endothelial Cadherin
Arch Ophthalmol, August 1, 2008; 126(8): 1082 - 1088.
[Abstract] [Full Text] [PDF]


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