A Novel Small Molecule for the Prevention and Treatment of Diabetic Retinopathy

摘要 糖尿病视网膜病变(DR)在美国是导致失明的主要原因。目前，对DR的大多数治疗方法 仅适用于后期阶段，是侵入性的。抗血管内皮生长因子药物 对糖尿病视网膜病变和新生血管(NV)取得了令人印象深刻的治疗效果。然而，40%的患者 患有DR的患者对治疗反应不足。鉴于DR是一种多因素疾病，治疗 靶向单一致病因子(如血管内皮生长因子)显然不足以在所有DR中达到预期效果 病人。因此，开发新的、无创的、长效的、更有效的药理作用 迫切需要治疗糖尿病视网膜病变，特别是在疾病的早期阶段。这样做的总体目标是 第二阶段的项目是开发一种新的药物，用于过氧化物酶体增殖物激活的博士的口服药物治疗 受体α(PPARα)是一种配体激活的核受体，调节线粒体脂质β氧化和转录。 过氧化物酶清除细胞质中的过氧化氢。两项大型纵向临床研究报告 单独地，口服PPARα激动剂非诺贝特对糖尿病视网膜病变有很强的治疗效果 2例糖尿病患者。这是第一个被证实对DR患者有效的口服药物。在动物临床前研究中 DR模型，药物激活的PPARα已被证明可以减少视网膜病变 在DR中观察到(例如视网膜中的病理性新生血管、血管渗漏和炎症)，结果 具有深远的治疗效果。因此，PPARα为DR的治疗提供了一个新的靶点。 然而，目前还没有fda批准的pparα药物用于Dr.我们的药物化学团队已经 合成并鉴定了非贝特类喹啉衍生小分子A190，一种新型的PPARα激动剂 更具活力的活动。在SBIR第一阶段研究中，我们已经完成了原则证明研究，证明 在两种糖尿病动物模型上，A190的全身给药比非诺贝特更有效。这些研究 将A190确立为进一步开发的有前途的候选药物。第二阶段的拟议研究将 重点评价A190在两个物种(大鼠和兔)体内的安全性和毒理学。此外，长期- 口服A190的长期疗效将在DR模型中进行测试。这一第二阶段计划包括三个 明确的目标。具体目标1：评估和优化A190对糖尿病视网膜病变视网膜血管渗漏的疗效 模特们。具体目的2：测定A190的药代动力学及眼组织分布。特定目标 3：评估A190可能的眼部和全身毒性。这些研究将为以下工作提供必要的信息 A190作为DR的口服药物的IND使能研究和未来临床试验。

SUMMARY Diabetic retinopathy (DR) is a leading cause of blindness in the United States. Currently, most treatments for DR are only applicable at the late stage and are invasive. Anti-VEGF (vascular endothelial growth factor) agents have achieved impressive therapeutic effects against DR and neovascularization (NV). However, 40% of patients with DR have inadequate responses to the treatment. Given that DR is a multi-factorial disease, therapies that target one single pathogenic factor (such as VEGF) are clearly insufficient to achieve desired efficacy in all DR patients. Therefore, the development of novel, non-invasive, long-term and more effective pharmacological treatments for DR is urgently required, particularly at an early stage of the disease. The overall objective of this Phase II project is to develop a novel drug for the oral pharmacotherapy of DR. Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear receptor that regulates mitochondrial lipid β oxidation and peroxisome scavenge hydrogen peroxide in the cytoplasm. Two large and longitudinal clinical studies reported independently that oral administration of PPARα agonist fenofibrate has robust therapeutic effect on DR in type 2 diabetic patients. This is the first oral drug with proven effect in DR patients. In preclinical studies with animal models of DR, pharmacological activation of PPARα has been shown to decrease retinal pathologies typically observed in DR (e.g. pathogenic neovascularization, vascular leakage and inflammation in the retina), resulting in a profound therapeutic effect. Thus, PPARα represents a novel therapeutic target for the treatment of DR. However, there are currently no FDA-approved PPARα drugs for DR. Our medicinal chemistry team has synthesized and identified a non-fibrate, quinoline-derived small molecule A190, a novel PPARα agonist with more potent activity. In SBIR Phase I studies, we have completed Proof-of-Principle studies demonstrating that systemic administration of A190 is more effective than fenofibrate on two diabetic animal models. These studies established A190 as a promising drug candidate for further development. The proposed research in Phase II will focus on evaluating in vivo safety and toxicology of A190 in two species (rats and rabbits). In addition, the long- term efficacy of orally administered A190 will be tested in DR models. This Phase II program includes three specific Aims. Specific Aim 1: Evaluate and optimize the efficacy of A190 on retinal vascular leakage in DR models. Specific Aim 2: Determine the pharmacokinetics of A190 and its ocular tissue distribution. Specific Aim 3: Assess possible ocular and systemic toxicities of A190. These studies will provide essential information for IND-enabling studies and future clinical trials of A190 as an oral drug for DR.