Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization.
OBJECTIVE
To evaluate the pharmacologic activity and tolerability of JSM6427, a potent and first selective small-molecule inhibitor of integrin alpha5beta1, in monkey and rabbit models of choroidal neovascularization (CNV).


METHODS
JSM6427 selectivity for alpha5beta1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor-induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 microg) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 weeks. Fluorescein angiography was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histologically in both models; additional assessments in monkeys included electroretinography, biomicroscopy, pathological examination, and analysis of JSM6427 pharmacokinetics.


RESULTS
JSM6427 was highly selective for the alpha5beta1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor-induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation.


CONCLUSIONS
Intravitreal JSM6427 provided dose-dependent inhibition of CNV in monkey and rabbit experimental models.


CONCLUSIONS
JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.
Zahn
Grit
G
Jerini AG, Invalidenstrasse 130, 10115 Berlin, Germany. grit.zahn@gmx.net
Vossmeyer
Dörte
D
Stragies
Roland
R
Wills
Margaret
M
Wong
Corinne G
CG
Löffler
Karin U
KU
Adamis
Anthony P
AP
Knolle
Jochen
J
D000631:Aminopyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004596:Electroretinography; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D005451:Fluorescein Angiography; D007267:Injections; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014822:Vitreous Body; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000631:Aminopyridines; D020533:Angiogenesis Inhibitors; D039081:Integrin alpha5beta1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D015091:beta-Alanine