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。糖尿病性视网膜病（DR）是糖尿病的常见并发症，是 劳动人口的失明。目前，> 40％的患者人群无法对黄金标准做出反应 抗VEGF直接眼内注射治疗。与当前优越或协同作用的新疗法 方法对患者具有很高的价值。与当前的治疗方案不同，新方法应非 侵入性（进入眼睛），负担得起，不依赖专业设施。我们的研究计划试图 开发小分子PPARα激动剂作为DR的第一类治疗。 PPARα激动剂的承诺为 在人类临床试验中已经证实了一种治疗DR的新型策略，其中Fenobibrate（Feno），A 临床上使用的高脂血症药物，暴露于DR和视网膜的强大保护作用 2型糖尿病患者的新血管化（NV）。我们已经确定FENO的受保护作用是 与降脂活性无关，而是由于其PPARα的激动而引起的。 feno但是， 视网膜分布差，PPARα的亲和力/选择性低以及相关剂量限制性毒性的毒性较低 这将限制其用作博士疗法。最近，我们确定了一类新的非纤维化PPARα激动剂 这表明在视网膜血管中的体外和暴露效率方面提高了效力和选择性 泄漏DR动物模型（I.P.给药）。全部总计，这些数据提供了概念证明，并且清楚 证明1）PPARα在DR的主要临床特征和2）非纤维化相关的临床特征中保持关键作用 PPARα激动剂具有改善的物理特性和眼部分布具有很高的承诺 DR的第一类治疗选择。具体目标。 （1）基于结构的命中以优化新颖 PPARα激动剂； （2）确定新设计和合成类似物的效力和效率； （3）定义 PPARα激动剂对氧化作用的受保护作用的下游分子机制（S） DR的压力和炎症。研究设计。我们将利用实验室开发的硅PPARα模型的利用 指导改进的激动剂的设计。合成的类似物将在体外生化和细胞中评估 PPARα效力，激动剂水平和同工型选择性的测定。符合预定义指标的化合物 将进行辅助测定，以确定抗血管生成，抗氧化和神经保护作用 体外。将评估顶部化合物的效率，以防止残留的白细胞症，内皮障碍，周围 动物模型中的损失，血管泄漏，视觉功能和神经视网膜凋亡。表现最高的化合物 将用于详细研究来定义受保护的下游分子机制 PPARα激动剂对DR的主要病因驱动因素的影响。这项研究很重要，因为它将 提供新的治疗潜在客户和一种新颖的方法来治疗DR，从而解决了紧迫的全球 需要。这项研究具有创新性，因为它试图为眼部提供小分子，无创选择 通常通过破坏性手术程序或生物制剂的眼内注射治疗的疾病。