A nitric oxide synthase inhibitor for uveitis

描述（由申请人提供）：类固醇治疗前葡萄膜有效，但长期使用后经常与白内障形成相关。开发一种有效的类固醇替代品，没有这些安全问题，将是一个重大的进步。在第一阶段SBIR，我们提出了一种新的治疗候选治疗葡萄膜炎的基础上，引入一种专有的新型抑制剂的诱导型一氧化氮（NO）合酶（iNOS），一种酶的从头上调表达的释放造成伤害的NO量，并产生炎症性损伤葡萄膜炎。我们的开发候选物GED（胍基乙基二硫化物）选择性抑制iNOS活性并清除过氧硝酸盐，这是一种由NO和超氧化物反应形成的有毒氧化剂。在内毒素诱导的葡萄膜炎（EIU）大鼠模型中，GED被证明在全身或局部给药（作为0.3%的眼药水）时非常有效。我们还进行了研究，表明GED治疗是安全的， 如阴性体外和体内遗传毒理学试验所证明的，大鼠和犬全身给予GED的诺埃尔比眼科使用的潜在吸收药物高100倍，培养的上皮细胞中无细胞毒性，用超治疗（10%）GED滴眼液激发的兔中无眼损伤。在目前的2期SBIR中，我们将进行安全性和有效性研究，以便将GED推进到可以开始人体临床试验的阶段。为此，我们将首先在家兔中测试GED，以在经典葡萄膜炎模型中建立治疗机会窗，并将在60天和6个月重复给药研究中测试化合物的安全性。后一项研究对于确定GED与类固醇相比不会诱导白内障形成至关重要。目前III期SBIR申请中提出的研究结果将为FDA批准的IND进行I/II期临床试验提供基础。

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.