Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization.

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Zahn G, Vossmeyer D, Stragies R, Wills M, Wong CG, Loffler KU, Adamis AP, Knolle J

Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization.

Arch Ophthalmol. 2009 Oct;127(10):1329-35. doi: 10.1001/archophthalmol.2009.265.

PubMed ID
19822850 [ View in PubMed
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Abstract

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. CLINICAL RELEVANCE: JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.

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