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ENDOCRINE AND DIABETES

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

Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania (R.J.S., W.A.K., S.G., B.L.D., L.L., R.W.A.T., Z.Z., N.H., R.A.G., D.L.J., B.E.M., B.P.D.); Neuromed Pharmaceuticals, Vancouver, British Columbia, Canada (R.A.G.); University of Florida, Gainesville, Florida (M.B.G., L.C.S.); Pharmaceutical Research Institute at Albany College of Pharmacy, Albany, New York (S.A.M.); and Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts (S.E.B., A.C.C.)

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,β,S)-1,2,3,4-Tetrahydro-β-[[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 _Vβ₃ and _Vβ₅ binding to vitronectin in the low nanomolar range, it has excellent selectivity over integrins _IIbβ₃ and ₅β₁, 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.

Address correspondence to: Rosemary J. Santulli, Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Rds., Spring House, PA 19477-0776. E-mail: rsantull{at}prdus.jnj.com