New Thalidomide Analogs for Retinal Neovacularization

描述(申请人提供)：糖尿病视网膜病变是糖尿病的常见并发症，也是发达国家致盲的主要原因。糖尿病视网膜病变有两种主要的损害视力的病理改变：由视网膜血管通透性增加引起的糖尿病黄斑水肿(DME)和视网膜内异常血管生成或视网膜新生血管(NV)。目前，还没有有效的药物治疗DME和视网膜NV。血管内皮生长因子(VEGF)的过度表达被认为在DME和视网膜NV的发生发展中起关键作用。沙利度胺及其类似物已被证明具有抗血管生成活性，并已用于治疗多发性肌瘤和几种癌症。由于沙利度胺及其类似物抗血管生成活性较弱，其在视网膜新生血管疾病治疗中的应用受到限制。需要具有更好的抗血管生成活性的新化合物。最近，我们的合作者用芳基取代了沙利度胺的戊二胺环，合成了一系列新型的沙利度胺类似物。体外试验表明，其中三个类似物比沙利度胺和其他已有类似物具有更强的抗肿瘤生长活性。我们推测，这些类似物在治疗DME和视网膜NV方面具有治疗潜力。 这一第一阶段项目将作为一项概念验证研究，以证实三种沙利度胺类似物对氧诱导视网膜病变(OIR)大鼠视网膜NV的抗血管生成作用。OIR是一种常用的视网膜NV动物模型。我们将确定这些化合物是否可以防止视网膜NV的发展并阻止其进展。由于这些化合物阻断了HIF-1的表达，HIF-1是上调血管内皮生长因子表达的关键转录因子，我们推测它们也可能降低糖尿病视网膜的血管通透性。这些化合物对链脲佐菌素诱导的糖尿病大鼠视网膜血管通透性的影响将被确定。这些化合物的效果将与沙利度胺进行比较。这些研究不仅将揭示这些化合物在治疗视网膜NV和DME方面的潜在疗效，而且还将确定它们是否比沙利度胺更有效。第一阶段项目将为第二阶段研究这些化合物的机制、传递途径、新陈代谢和毒性奠定坚实的基础。因此，该项目具有开发新型抗血管生成药物的潜力。

DESCRIPTION (provided by applicant): Diabetic retinopathy is a common complication of diabetes mellitus and a leading cause of blindness in the developed countries. There are two major pathological changes which impair vision in diabetic retinopathy: diabetic macular edema (DME) resulting from increased retinal vascular permeability and abnormal angiogenesis in the retina or retinal neovascularization (NV). Currently, there is no effective drug treatment for DME and retinal NV. Over-expression of vascular endothelial growth factor (VEGF) is believed to play a critical role in the development of DME and retinal NV. Thalidomide and its analogs have been shown to have anti-angiogenic activities and have been used for the treatments of multiple myenoma and several cancers. The application of thalidomide and its existing analogs in the treatment of retinal neovascular disorders is limited due to their weak anti-angiogenic activities. Novel compounds with improved anti-angiogenic activities are needed. Recently, our collaborator has synthesized a series of novel thalidomide analogs by substituting the glutaramide ring of thalidomide with an aromatic group. The in vitro assays have shown that three of these analogs have more potent anti-agiogenic activity than thalidomide and other existing analogs. We hypothesize that these analogs have therapeutic potential in the treatment of DME and retinal NV. This Phase I project will serve as a proof-of-concept study to confirm the anti-angiogenic effect of the three thalidomide analogs on retinal NV in a rat model of oxygen-induced retinopathy (OIR), a commonly used animal model of retinal NV. We will determine if these compounds can prevent the development of retinal NV and arrest its progression. As these compounds block the expression of HIF-1, a key transcription factor up-regulating VEGF expression, we hypothesize that they may also reduce vascular permeability in diabetic retina. The effect of these compounds on retinal vascular permeability will be determined in steptozotocin-induced diabetic rats. The effect of these compounds will be compared with that of thalidomide. These studies will not only reveal the therapeutic potenital of these compounds in the treatment of retinal NV and DME, but also determine if they are more potent than thalidomide. The Phase I project will lay a solid ground for the Phase II to investigate the mechanism, delivery routes, metabolism and toxicities of these compounds. Therefore, this project has potential to develop novel anti-angiogenic drugs with improved potency.