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

Full 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.

Author information

Author/s: Zahn, Grit (G); Vossmeyer, Dörte (D); Stragies, Roland (R); Wills, Margaret (M); Wong, Corinne G (CG); Löffler, Karin U (KU); Adamis, Anthony P (AP); Knolle, Jochen (J);

Affiliation: Jerini AG, Invalidenstrasse 130, 10115 Berlin, Germany. grit.zahn(-atsign-)gmx.net

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Archives of ophthalmology (Arch Ophthalmol), published in United States. (Language: eng)

Reference: 2009-Oct; vol 127 (issue 10) : pp 1329-35

Dates: Created 2009/10/13; Completed 2009/11/02;

PMID: 19822850, status: MEDLINE (last retrieval date: 11/2/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Associated Chemicals: Aminopyridines (0) ; Angiogenesis Inhibitors (0) ; Integrin alpha5beta1 (0) ; Vascular Endothelial Growth Factor A (0) ; Fibroblast Growth Factor 2 (103107-01-3) ; beta-Alanine (107-95-9)

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