A nitric oxide synthase inhibitor for uveitis

描述(申请人提供)：类固醇治疗前葡萄膜是有效的，但经常与长期使用后的白内障形成有关。开发一种有效的类固醇替代品，而不存在这些安全问题，将是一个实质性的进步。在I期SBIR中，我们提出了一种新的治疗葡萄膜炎的候选方案，该方案基于引入一种专利的新型诱导型一氧化氮合酶(INOS)抑制剂，iNOS是一种酶，其重新上调的表达解释了NO的损害量的释放，并在葡萄膜炎中产生炎性损伤。我们开发的候选化合物GED(胍基乙基二硫化物)选择性地抑制iNOS活性并清除过氧硝酸盐，过氧硝酸酯是一种由NO和超氧化物反应形成的有毒氧化剂。在内毒素诱导性葡萄膜炎(EIU)的大鼠模型中，GED被证明是非常有效的，无论是全身给药还是局部给药(0.3%眼液)。我们还进行了一些研究，表明GED疗法是安全的， 根据阴性的体外和体内遗传毒理学分析，全身给药的大鼠和狗的NOEL是从眼部使用的潜在吸收药物的100倍，培养的上皮细胞没有细胞毒性，用超治疗(10%)GED眼液挑战的兔眼部损伤。在目前的第二阶段SBIR中，我们将进行安全性和有效性研究，以便将GED向前推进到可以开始人类临床试验的阶段。为此，我们将首先在兔身上测试GED，以建立经典葡萄膜炎模型的治疗机会窗，并将在60天和6个月的重复剂量研究中测试该化合物的安全性。后一项研究对于确定GED与类固醇不同，不会导致白内障的形成至关重要。目前的第三阶段SBIR申请中提出的研究结果将为FDA批准的IND进行第一/第二阶段临床试验提供基础。

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.