Small Molecule PPAR-alpha Agonism as a Novel Approach to Treat Eye Vascular Diseases

小分子 PPAR-α 激动剂作为治疗眼血管疾病的新方法

• 批准号: 10359598
• 负责人: Adam Scott Duerfeldt
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359598
• 关键词: Small; Molecule; PPAR; alpha; Agonism

Project Summary. Diabetic retinopathy (DR) is a common complication of diabetes and is the leading cause of blindness in the working population. Currently, >40% of the patient population fails to respond to gold-standard anti-VEGF direct intraocular injection treatments. New therapies that are superior to or synergistic with current approaches are of great value to patients. Unlike current treatment options, new approaches should be non- invasive (into the eye), affordable, and not reliant on specialized facilities. Our research program seeks to develop small molecule PPARα agonists as first-in-class treatments for DR. The promise of PPARα agonism as a novel strategy for treating DR has been confirmed in human clinical trials, wherein Fenofibrate (Feno), a clinically used drug for hyperlipidemia, exhibited robust protective effects against DR and retinal neovascularization (NV) in type 2 diabetic patients. We have determined that the protective effects of Feno are unrelated to its lipid-lowering activity, but rather result from its agonism of PPARα. Feno however, suffers from poor retinal distribution, low affinity/selectivity for PPARα, and chemotype related dose-limiting toxicities, all of which will limit its use as a DR therapy. Recently, we have identified a novel class of non-fibrate PPARα agonists that demonstrate improved potency and selectivity over Feno in vitro and exhibit efficacy in a retinal vascular leakage DR animal model (i.p. administration). All totaled, these data provide proof-of-concept and clearly demonstrate that 1) PPARα maintains critical roles in the major clinical features of DR and 2) Non-fibrate related PPARα agonists with improved physicochemical properties and ocular distribution have high promise to become first-in-class therapeutic options for DR. Specific Aims. (1) Structure-based hit to lead optimization of novel PPARα agonists; (2) Determine the potency and efficacy of newly designed and synthesized analogs; (3) Define the downstream molecular mechanism(s) underlying the protective effects of PPARα agonism against oxidative stress and inflammation in DR. Study Design. We will leverage in silico PPARα models developed in our lab to guide the design of improved agonists. Synthesized analogs will be assessed in in vitro biochemical and cellular assays for PPARα potency, level of agonism, and isoform selectivity. Compounds meeting pre-defined metrics will be advanced to secondary assays to determine anti-angiogenic, anti-oxidative, and neuroprotective effects in vitro. Top compounds will be assessed for efficacy against retinal leukostasis, endothelial impairment, pericyte loss, vascular leakage, visual function, and neuroretinal apoptosis in animal models. Top performing compounds will be utilized for detailed studies to define the downstream molecular mechanisms underlying the protective effects of PPARα agonism against the major etiological drivers of DR. The research is significant in that it will provide new therapeutic leads and a novel approach for the treatment of DR, thus addressing a pressing global need. The research is innovative in that it seeks to provide small molecule, non-invasive options for ocular conditions typically treated with destructive surgical procedures or intraocular injections of biologics.

项目摘要。糖尿病视网膜病变(DR)是糖尿病的常见并发症，也是糖尿病的主要病因。 工作人口中的失明。目前，40%的患者对黄金标准没有反应。 抗血管内皮生长因子直接眼内注射治疗。优于现有疗法或与现有疗法协同的新疗法 手术入路对患者有很大的价值。与目前的治疗方案不同，新的治疗方法应该是非 侵入性(进入眼睛)，负担得起，不依赖专门的设施。我们的研究计划寻求 开发小分子PPARα激动剂作为DR的一流治疗药物PPARα激动剂有望成为 一种治疗DR的新策略已在人体临床试验中得到证实，其中非诺贝特(FeNO)，一种 临床上用于治疗高脂血症的药物，对糖尿病视网膜病变和视网膜表现出强大的保护作用 2型糖尿病患者的新生血管形成。我们已经确定了FeNO的保护作用是 与其降脂活性无关，而是其对PPARα的激活作用所致。然而，FeNO却患有 视网膜分布不良，对PPARα的亲和力/选择性低，以及与化学型相关的剂量限制毒性，所有这些都是 这将限制其作为DR疗法的使用。最近，我们发现了一类新的非贝特pparα激动剂。 在体外表现出比FeNO更好的效力和选择性，并在视网膜血管中表现出有效性 渗漏DR动物模型(I.P.行政管理)。总而言之，这些数据提供了概念验证和明确的 证明1)PPARα在DR的主要临床特征和2)非贝特相关的临床特征中保持关键作用 具有改善的物理化学性质和眼部分布的PPARα激动剂有望成为 针对特定目标医生的一流治疗方案。(1)基于结构的命中引领小说的优化 PPARα激动剂；(2)测定新设计和合成的类似物的效力和疗效；(3)确定 PPARα激动剂抗氧化保护作用的下游分子机制(S) 博士研究设计中的压力和炎症。我们将在实验室开发的Silico PPARα模型中利用 指导改进的激动剂的设计。人工合成的类似物将在体外生化和细胞内进行评估。 PPARα效价、激动度和异构体选择性的测定。符合预定义指标的化合物 将进入二次检测以确定抗血管生成、抗氧化和神经保护作用 在试管中。顶级化合物将被评估对视网膜白血球停滞、内皮损伤、周细胞的疗效 动物模型中的丢失、血管渗漏、视功能和神经视网膜细胞凋亡。性能最好的化合物 将被用于详细的研究，以确定潜在的保护性下游分子机制 PPARα激动剂对DR主要病因的影响这项研究具有重要意义，因为它将 为DR的治疗提供新的治疗线索和新的方法，从而解决全球紧迫的 需要。这项研究的创新之处在于，它试图为眼部提供小分子、非侵入性的选择 通常采用破坏性外科手术或眼内注射生物制剂治疗的情况。