Studies with an orally bioavailable αV integrin antagonist in animal models of ocular vasculopathy: Retinal neovascularization in mice and retinal vascular permeability in diabetic rats

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

Research output: Contribution to journalArticle

37 Scopus citations

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 α5β 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 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.

Original languageEnglish (US)
Pages (from-to)894-901
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number3
DOIs
StatePublished - Mar 1 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Santulli, R. J., Kinney, W. A., Ghosh, S., DeCorte, B. L., Liu, L., Tuman, R. W. A., Zhou, Z., Huebert, N., Bursell, S. E., Clermont, A. C., Grant, M. B., Shaw, L. C., Mousa, S. A., Galemmo, R. A., Johnson, D. L., Maryanoff, B. E., & Damiano, B. P. (2008). Studies with an orally bioavailable αV integrin antagonist in animal models of ocular vasculopathy: Retinal neovascularization in mice and retinal vascular permeability in diabetic rats. Journal of Pharmacology and Experimental Therapeutics, 324(3), 894-901. https://doi.org/10.1124/jpet.107.131656