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

被引：39

作者：

Santulli, Rosemary J. ^{[1
]}

Kinney, William A. ^{[1
]}

Ghosh, Shyamali ^{[1
]}

DeCorte, Bart L. ^{[1
]}

Liu, Li ^{[1
]}

Tuman, Robert W. A. ^{[1
]}

Zhou, Zhao ^{[1
]}

Huebert, Norman ^{[1
]}

Bursell, Sven E. ^{[5
]}

Clermont, Alan C. ^{[5
]}

Grant, Maria B. ^{[3
]}

Shaw, Lynn C. ^{[3
]}

Mousa, Shaker A. ^{[4
]}

Galemmo, Robert A., Jr. ^{[1
,2
]}

Johnson, Dana L. ^{[1
]}

Maryanoff, Bruce E. ^{[1
]}

Damiano, Bruce P. ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev, Spring House, PA 19477 USA

[2] Neuromed Pharmaceut, Vancouver, BC, Canada

[3] Univ Florida, Gainesville, FL USA

[4] Albany Coll Pharm, Pharmaceut Res Inst, Albany, NY USA

[5] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2008年 / 324卷 / 03期

关键词：

D O I：

10.1124/jpet.107.131656

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The alpha(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 alpha(v) antagonist, and an oral drug would offer a distinct advantage over current therapies. (3,S,beta,S)-1,2,3,4-Tetrahydro-beta-[[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 alpha(v) antagonist derived from the arginine-glycine-asparagine 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, it has excellent selectivity over integrins alpha(11b)beta(3) and alpha(5)beta(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 alpha(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.

引用

页码：894 / 901

页数：8

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