Novel Combretastatin A4 analogs for Treatment of Retinal Neovascularization

用于治疗视网膜新生血管的新型 Combretastatin A4 类似物

• 批准号: 7271495
• 负责人: Danyang Chen
• 金额: $ 23.74万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271495
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adverse effects; Affect; African; Angiogenesis Inhibitors; Animal Model; Attention; Binding; Biological Assay; Blindness; Blood Vessels; Blood capillaries; CDK6-associated protein p18; Cancer cell line; Capillary Endothelial Cell; Cell Proliferation; Cells; Choroidal Neovascularization; Combretastatin A-4; Combretastatin A4 Phosphate; Combretum; Complications of Diabetes Mellitus; Contralateral; Count; Developed Countries; Developing Countries; Development; Diabetic Retinopathy; Disease; Disruption; Dose; Dose-Limiting; Drug Kinetics; Drug usage; Endothelial Cells; Eye; Fluorescein Angiography; Funding; Future; Goals; Growth; Hemorrhage; Human; In Vitro; Incentives; Inhibitory Concentration 50; Injection of therapeutic agent; Marketing; Measures; Migration Assay; Modeling; Oxygen; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Population; Principal Investigator; Proliferating; Protein Tyrosine Kinase; Range; Rattus; Receptor Signaling; Research; Retina; Retinal; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; Role; Route; SU 5416; Series; Signal Transduction; Solid; Solid Neoplasm; Structure; Structure-Activity Relationship; Therapeutic; Toxic effect; Tube; Tubulin; Tubulin Binding Agent; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Water; analog; angiogenesis; base; capillary; cell growth; cell motility; concept; day; desire; improved; in vivo; inhibitor/antagonist; migration; neovascularization; novel; ocular neovascularization; polymerization; postnatal; prevent; programs; proliferative diabetic retinopathy; research study; retinal angiogenesis; tumor

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a common complication of diabetes mellitus and a leading cause of blindness in developed countries. Abnormal angiogenesis in the retina or retinal neovascularization (NV) is one of the major pathological changes in DR. Retinal NV can ultimately result in severe vitreous cavity hemorrhage and/or retinal detachment, leading to severe loss of vision. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of retinal NV. Targeting VEGF receptor (VEGFR) or disruption of VEGF signaling is believed to be a most promising strategy for the pharmacological therapy of ocular NV. Therefore, searching for and developing new drugs to block retinal NV via targeting VEGF signaling or VEGFR have initiated a major research effort with potential of producing novel, potent, efficacious, and marketable drugs for the treatment of DR. Combretastatin A4 (CA4) is a natural tubulin-binding molecule, which has received special attention in the last few years. Combretastatin A4 phosphate (CA4P), a water-soluble prodrug of CA4, has both anti-proliferative and anti-angiogenic activities. CA4P also showed potential inhibition of retinal NV. However, high doses of CA4P caused significant toxicities. Four phase I clinical trials in humans demonstrated the side effects and dose-limiting toxicities of CA4P. Thus, new CA4 analogs with improved anti-angiogenc activities and less side effects are desired. A collaborator of this project has synthesized a series of novel CA4 analogs using SU5416 (a VEGFR signaling inhibitor) as a template. Among 25 novel compounds studied, two promising CA4 analogs displayed more potent anti-tumor activities than CA4 and SU5416. We hypothesize that the novel CA4 analogs have therapeutic potential in the treatment of retinal NV. Our objective is to develop more potent, selective anti-angiogenic drugs, which can prevent and arrest retinal NV. The Phase I project will determine the efficacy of these novel compounds on angiogenesis. Our in vitro studies will evaluate whether these new compounds have anti-angiogenic activity. We will also determine the effect of these novel compounds on retinal NV in oxygen-induced retinopathy (OIR) rat model, which is a commonly used model of proliferative diabetic retinopathy. These studies may identify novel compounds with therapeutic potential for the treatment of retinal NV. This proof-of-concept study will allow future Phase II project to study their toxicities and pharmacokinetics. Therefore, this project, if funded, has potential to generate marketable products for the treatment of a major blinding disease. As retinal NV affects a large population, and as there is no effective drug available on the market, these new anti-angiogenic drugs should have great commercial potential. Retinal neovascularization is a major pathological change leading to vision loss in diabetic retinopathy, which is a leading cause of blindness in the world. Our goal is to develop novel anti-angiogenic drugs for the treatment of retina neovascularization. In this project, we will study the effects of two novel CA4 analogs selected from 25 new compounds on retinal angiogenesis in vitro and in vivo. This proof-of-concept study represents the first step in developing new anti-angiogenic drugs using these CA4 analogs.

描述（申请人提供）：糖尿病视网膜病变（DR）是糖尿病的常见并发症，也是发达国家失明的主要原因。视网膜异常血管生成或视网膜新生血管(NV)是DR的主要病理改变之一。视网膜 NV 最终会导致严重的玻璃体腔出血和/或视网膜脱离，导致视力严重丧失。血管内皮生长因子（VEGF）在视网膜NV的发病机制中发挥着关键作用。靶向 VEGF 受体 (VEGFR) 或破坏 VEGF 信号传导被认为是眼部 NV 药物治疗最有前途的策略。因此，寻找和开发通过靶向 VEGF 信号传导或 VEGFR 来阻断视网膜 NV 的新药已经启动了一项重大研究工作，有潜力生产用于治疗 DR 的新型、强效、有效和可销售的药物。考布他汀 A4 (CA4) 是一种天然的微管蛋白结合分子，近年来受到特别关注。 Combretastatin A4 磷酸盐 (CA4P) 是一种 CA4 的水溶性前药，具有抗增殖和抗血管生成活性。 CA4P 还表现出对视网膜 NV 的潜在抑制作用。然而，高剂量的 CA4P 会引起显着的毒性。四项人体 I 期临床试验证明了 CA4P 的副作用和剂量限制毒性。因此，需要具有改善的抗血管生成活性和更少副作用的新CA4类似物。该项目的合作者以SU5416（一种VEGFR信号抑制剂）为模板合成了一系列新型CA4类似物。在研究的 25 种新型化合物中，两种有前景的 CA4 类似物显示出比 CA4 和 SU5416 更有效的抗肿瘤活性。我们假设新型 CA4 类似物在治疗视网膜 NV 方面具有治疗潜力。我们的目标是开发更有效的、选择性的抗血管生成药物，以预防和阻止视网膜 NV。第一阶段项目将确定这些新型化合物对血管生成的功效。我们的体外研究将评估这些新化合物是否具有抗血管生成活性。我们还将确定这些新型化合物对氧诱导视网膜病变 (OIR) 大鼠模型（一种常用的增殖性糖尿病视网膜病变模型）中视网膜 NV 的影响。这些研究可能会鉴定出具有治疗视网膜 NV 潜力的新化合物。这项概念验证研究将使未来的二期项目能够研究其毒性和药代动力学。因此，该项目如果获得资助，有可能产生用于治疗重大致盲疾病的适销产品。由于视网膜NV影响的人群较多，且市场上尚无有效药物，这些新型抗血管生成药物应该具有巨大的商业潜力。视网膜新生血管形成是导致糖尿病视网膜病变视力丧失的主要病理变化，糖尿病视网膜病变是世界上导致失明的主要原因。我们的目标是开发新型抗血管生成药物来治疗视网膜新生血管。在这个项目中，我们将研究从 25 种新化合物中选出的两种新型 CA4 类似物在体外和体内对视网膜血管生成的影响。这项概念验证研究代表了使用这些 CA4 类似物开发新的抗血管生成药物的第一步。