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

总结 糖尿病视网膜病变（DR）是美国致盲的主要原因。目前，大多数DR治疗 仅适用于晚期，并且是侵入性的。抗VEGF（血管内皮生长因子）药物 已经取得了令人印象深刻的治疗效果，对DR和新血管形成（NV）。40%的患者 DR患者对治疗的反应不足。鉴于DR是一种多因素疾病， 靶向单一致病因子（如VEGF）显然不足以在所有DR中获得所需功效 患者因此，开发新型、无创、长效、更有效的药理学 迫切需要DR的治疗，特别是在疾病的早期阶段。本报告的总体目标 II期项目是开发一种用于DR的口服药物治疗的新药。 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， 过氧化物酶体是细胞质中的过氧化氢。两项大型纵向临床研究报告 独立地，口服给予PPARα激动剂非诺贝特对型DR具有稳健治疗效果， 2例糖尿病患者。这是第一个在DR患者中证明有效的口服药物。动物临床前研究 在DR模型中，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（例如视网膜中的致病性新血管形成、血管渗漏和炎症），导致 有着深远的治疗效果。因此，PPARα是DR治疗的新靶点。 然而，目前还没有FDA批准的用于DR的PPARα药物。 合成并鉴定了一种非贝特类、喹啉衍生的小分子A190，一种新型的PPARα激动剂， 更有力的活动。在SBIR I期研究中，我们已经完成了原理验证研究，证明 在两种糖尿病动物模型中，A190全身给药比非诺贝特更有效。这些研究 确定A190为进一步开发的有希望的候选药物。第二阶段的拟议研究将 重点评价A190在两个种属（大鼠和家兔）中的体内安全性和毒理学。此外，长- 将在DR模型中测试口服施用A190的长期功效。第二阶段计划包括三个 具体目标。具体目标1：评估和优化A190对DR中视网膜血管渗漏的有效性 模型具体目的2：确定A190的药代动力学及其眼组织分布。具体目标 3：评估A190可能的眼部和全身毒性。这些研究将为以下方面提供重要信息： IND使能研究和A190作为DR口服药物的未来临床试验。

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.