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.
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(IIb)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.
Santulli
Rosemary J
RJ
Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Rds., Spring House, PA 19477-0776, USA. rsantull@prdus.jnj.com
Kinney
William A
WA
Ghosh
Shyamali
S
Decorte
Bart L
BL
Liu
Li
L
Tuman
Robert W A
RW
Zhou
Zhao
Z
Huebert
Norman
N
Bursell
Sven E
SE
Clermont
Alan C
AC
Grant
Maria B
MB
Shaw
Lynn C
LC
Mousa
Shaker A
SA
Galemmo
Robert A
RA
Johnson
Dana L
DL
Maryanoff
Bruce E
BE
Damiano
Bruce P
BP
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011247:Pregnancy; D011804:Quinolines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000188:drug therapy / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D039564:Integrin alphaV; C527479:JNJ-26076713; D009287:Naphthyridines; D011804:Quinolines