Small molecule drugs for treatment of dry age-related macular degeneration

治疗干性年龄相关性黄斑变性的小分子药物

• 批准号: 8284309
• 负责人: Konstantin Petrukhin
• 金额: $ 20.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284309
• 关键词: Adverse effects; Affect; Age related macular degeneration; All-Trans-Retinol; Animal Model; Apoptosis Promoter; Atrophic; Binding; Binding Sites; Biological Assay; Biological Markers; Blindness; Blood Circulation; Cells; Clinical; Complex; Cytoplasmic Granules; Data; Developed Countries; Development; Dose; Down-Regulation; Drug Kinetics; FDA approved; FGR gene; Fluorescence Resonance Energy Transfer; Functional disorder; Goals; Health; Hybrids; Lead; Legal Blindness; Ligands; Lipofuscin; Malignant Neoplasms; Mediating; Metabolic; Modeling; Mus; Neurodegenerative Disorders; Neurons; Nuclear Receptors; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase I Clinical Trials; Photobleaching; Photoreceptors; Poison; Prealbumin; Production; Proteins; Reporting; Retina; Retinal Cone; Retinoids; Retinol Binding Proteins; Safety; Serum; Site; Specificity; Staging; Structure of retinal pigment epithelium; Testing; Wallerian Degeneration; base; cell type; clinical efficacy; cytotoxic; glomerular filtration; in vitro Assay; inhibitor/antagonist; macula; miniaturize; pre-clinical; preclinical efficacy; retinal rods; small molecule; treatment strategy; uptake; visual cycle

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of legal blindness in the US. There is no FDA-approved treatment for the most prevalent dry (atrophic) form of AMD. Dry AMD represents a slowly progressing neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina called macula. Dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE) which induce secondary degeneration of photoreceptor cells. Excessive accumulation of lipofuscin granules in RPE is thought to cause degeneration of RPE and adjacent photoreceptors in AMD retinas. The major cytotoxic component of RPE lipofuscin is a pyridinium bisretinoid A2E which is formed as a by-product of a properly functioning visual cycle. It was suggested that visual cycle inhibitors may reduce the formation of A2E/lipofuscin and prolong RPE and photoreceptor survival In AMD. Rates of the visual cycle and A2E production depend on the influx of all-trans retinol from serum to the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex in serum is required for retinol uptake from circulation to the RPE. Without Interacting with TTR, the RBP4-retlnol complex is rapidly cleared from circulation due to glomerular filtration. Retinol-binding site on RBP4 is sterically proximal to the Interface mediating the RBP4-TTR interaction. Non-toxic compounds that compete with serum retinol for binding to RBP4 while blocking the RBP4-TTR interaction would reduce serum retinol, slow down the visual cycle, and inhibit formation of cytotoxic A2E. Two chemically distinct compounds known to be antagonists of RBP4-TTR interaction are proposed for medicinal chemistry optimization in the current study. The overall goal of the proposed project is to develop potent and selective RBP4 antagonists with pre-clinical efficacy, pharmacokinetic, and safety profiles supporting testing of optimized RBP4 antagonists in Phase I clinical trials. To achieve this goal, the studies outlined In this proposal will seek to conduct medicinal chemistry optimization of two compounds using a battery of primary, secondary and counter-screen assays for assessing compound potency and specificity (Specific Aim 1) and to assess preclinical efficacy of candidate compounds in appropriate animal models at different stages of compound optimization (Specific Aim 2).

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是美国法律失明的最常见原因。对于最普遍的干燥（萎缩）AMD，没有FDA批准的治疗方法。干燥的AMD代表了一种缓慢发展的神经退行性疾病，其中专门的神经元（杆和锥形感受器）死亡的视网膜中央部分被称为黄斑。干燥AMD是由视网膜色素上皮（RPE）异常引起的，该视网膜色素上皮（RPE）诱导了感光细胞的继发性变性。 RPE中脂肪霉素颗粒的过度积累被认为会导致AMD视网膜中RPE和相邻的感光体变性。 RPE脂肪霉素的主要细胞毒性成分是吡啶双丁素A2E，形成为正常运行的视觉周期的副产品。据建议，视觉周期抑制剂可能会减少A2E/脂肪霉素的形成，并延长AMD中的RPE和感光受体存活。视觉周期和A2E产生的速率取决于全反元素从血清到RPE的涌入。在血清中摄入循环到RPE的视网膜摄取需要，需要在血清中形成三级视黄醇结合蛋白4（RBP4） - 转氨酸蛋白（TTR） - 返回醇复合物。在不与TTR相互作用的情况下，由于肾小球过滤引起的RBP4-逆转录复合物被迅速清除。 RBP4上的视黄醇结合位点在空间上与介导RBP4-TTR相互作用的界面近端。与血清视网膜竞争的无毒化合物在阻断RBP4-TTR相互作用的同时与RBP4结合，将减少血清视黄醇，减慢视觉周期并抑制细胞毒性A2E的形成。在当前研究中，提出了两种已知是RBP4-TTR相互作用的拮抗剂的化学化合物。拟议项目的总体目标是开发具有临床前功效，药代动力学和安全性的有效和选择性的RBP4拮抗剂，以支持I期临床试验中优化的RBP4拮抗剂的测试。为了实现这一目标，该提案中概述的研究将寻求使用一台原代，次级和反屏幕测定法对两种化合物进行药物化学优化，以评估复合效能和特异性（特定目的1）（具体目的1）并评估候选化合物在适当的动物模型中在不同动物模型的不同阶段的临床上疗效（特定目标2）。