New Thalidomide Analogs for Retinal Neovacularization

用于视网膜新空泡化的新型沙利度胺类似物

• 批准号: 6936106
• 负责人: KANGMO LU
• 金额: $ 14.98万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936106
• 关键词: analog; angiogenesis; diabetic retinopathy; drug design /synthesis /production; drug screening /evaluation; hypoxia inducible factor 1; laboratory rat; oxygen; retina; thalidomide; vascular endothelial growth factors

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.

描述（由申请人提供）：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性黄斑水肿（DME）和视网膜血管生成异常或视网膜新生血管（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，并已被用于治疗多发性肌瘤和几种癌症。沙利度胺及其现有类似物抗血管生成活性较弱，限制了其在视网膜新生血管疾病治疗中的应用。需要具有增强抗血管生成活性的新型化合物。最近，我们的合作者通过用芳香基团取代沙利度胺的戊二酰胺环合成了一系列新的沙利度胺类似物。体外实验表明，其中三种类似物比沙利度胺和其他现有类似物具有更强的抗衰老活性。我们假设这些类似物在治疗二甲醚和视网膜NV方面具有治疗潜力。