Abstract
The αV 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 αV 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 αV antagonist derived from the arginine-glycine-asparagine binding motif in the matrix protein ligands (e.g., vitronectin). This compound inhibits αVβ3 and αVβ5 binding to vitronectin in the low nanomolar range, it has excellent selectivity over integrins αIIbβ3 and α5β1, 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 αV 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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.131656.
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ABBREVIATIONS: AMD, age-related macular degeneration; DR, diabetic retinopathy; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; OIR, oxygen-induced model of retinopathy of prematurity; ROP, retinopathy of prematurity; RGD, arginine-glycine-asparagine; HMVEC, human microvascular endothelial cell; HUVEC, human umbilical vein endothelial cell; BSA, bovine serum albumin; PBS, phosphate-buffered saline; D5W, 5% dextrose in water; ANOVA, analysis of variance; CAM, chick chorioallantoic membrane; BW, body weight; BG, blood glucose; DM, diabetic mellitus; JNJ-26076713, (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; SB-267268, (4S)-2,3,4,5-tetrahydro-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-acetic acid; L-845704, (βS)-6-methoxy-β-[2-oxo-3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1-imidazolidinyl]-3-pyridinepropanoic acid.
- Received September 24, 2007.
- Accepted December 13, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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