A nitric oxide synthase inhibitor for uveitis

用于治疗葡萄膜炎的一氧化氮合酶抑制剂

• 批准号: 7082086
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 87.55万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082086
• 关键词: nitric; oxide; synthase; inhibitor; uveitis

DESCRIPTION (provided by applicant): Steroid treatment of anterior uveitus is effective but frequently associated with cataract formation after prolonged use. Development of an effective substitute for steroids, free of these safety concerns, would be a substantial advance. In a Phase I SBIR, we proposed a novel therapeutic candidate for treatment of uveitus, based on the introduction of a proprietary novel inhibitor of the inducible nitric oxide (NO) synthase (iNOS), an enzyme whose de novo upregulated expression accounts for the release of injurious quantities of NO and produces inflammatory injury in uveitis. Our development candidate, GED (guanidinoethyldisulfide), selectively inhibits iNOS activity and scavenges peroxynitrate, a toxic oxidant formed from the reaction of NO and superoxide. In a rat model of endotoxin-induced uveitis (EIU), GED proved highly effective when administered either systemically of topically (as an 0.3% ophthalmac solution). We also carried out studies that suggest that GED therapy is safe, as evidenced by negative in vitro and in vivo genotoxicology assays, a NOEL in rats and dogs for systemic GED administration 100-fold greater than the potential absorbed drug from ophthlamic use, a lack of cytotoxicity in cultured epithelial cells, and absenceof ocular injury in rabbits challenged with a supratherapeutic (10%) GED ophthalmic solution. In the current Phase 2 SBIR, we will conduct safety and efficacy studies in order to move GED forward to the stage where human clinical testing can begin. To this end, we will first test GED in rabbits to establish the therapeutic window of opportunity in a classic model of uveitis and we will test the safety of the compound in 60 day and 6 month repeat dose studies. The latter study will be critical to establish that GED, in contrast to steroids, does not induce cataract formation. The results of the studies proposed in the current Phase III SBIR application will provide the basis for an FDA-approved IND to perform Phase I/II clinical trials.

描述（由申请人提供）：类固醇治疗葡萄膜前部是有效的，但长期使用后常伴有白内障形成。开发一种没有这些安全隐患的类固醇的有效替代品将是一项重大进步。在I期SBIR中，我们提出了一种新的治疗葡萄膜炎的候选药物，基于引入一种专有的新型诱导性一氧化氮（NO）合成酶（iNOS）抑制剂，这种酶的新生表达上调导致了有害数量的NO的释放，并在葡萄膜炎中产生炎症损伤。我们开发的候选物质，GED (guanidinoethyldiulfide)，选择性地抑制iNOS活性并清除过氧硝酸盐，一种由NO和超氧化物反应形成的有毒氧化剂。在内毒素诱导的葡萄膜炎（EIU）大鼠模型中，GED被证明是非常有效的，无论是全身给药还是局部给药（作为0.3%的眼药水）。我们也进行了研究，表明GED疗法是安全的，