A Novel Small Molecule for The Prevention and Treatment of Age-Related Macular Degeneration

摘要 老年性黄斑变性(AMD)是美国湿性AMD老年人失明的主要原因 占AMD患者视力损失的90%，其特征是脉络膜新生血管 (CNV)。目前，AMD尚无治愈方法，可用的药物治疗主要集中在玻璃体内注射抗AMD药物。 血管内皮生长因子(VEGF)制剂。这些抗血管内皮生长因子的药物取得了令人印象深刻的治疗效果 大约70%的AMD患者对CNV的影响；然而，另外30%的患者仍然没有反应 抗血管内皮生长因子疗法。AMD是一种多因素疾病，治疗只针对单个分子(如 并不是所有的AMD患者都能从中受益。因此，新药的开发要多靶点 致病因素与单一化合物，是临床上尚未满足的需要。过氧化物酶体增殖物激活受体 α(PPARα)是一种广泛表达的配体激活的转录因子。最近的研究提供了强有力的证据 支持PPARα激动剂可以抑制视网膜和视网膜慢性炎症的恶性循环， 是AMD发病机制中的一个关键原因。此外，临床研究表明，口服治疗 非诺贝特(PPARα的激动剂)可显著减少视网膜激光光凝的需要 新生血管增加37%-40%。PPARα激动剂抑制新生血管和多发性硬化的过度生产 AMD动物模型中的炎症因子。同时，作为小分子，PPARα激动剂可以穿透 通过血-视网膜屏障，使其成为预防和治疗AMD的一种有前景的新型口服选择。 然而，非诺贝特的低特异性、低效性和剂量限制性毒性使其成为一种不理想的治疗方法 AMD选项。最近，我们团队自主设计、综合和筛选了200多个新的 PPARα激动剂，我们从其中鉴定出一种新的非贝特化合物A190，具有显著的改善 PPARα激动剂的效力和选择性(EC_(50)=∼37 nM)。它激活PPARα并上调其表达 PPARα靶基因在视网膜细胞中的表达，具有抗血管生成、抗炎和神经保护作用 效果优于非诺贝特。它还可以减少AMD模型中的视网膜炎症和血管渗漏。我们会 评价A190对AMD动物模型视网膜新生血管和炎症的影响。该项目将会实现 有两个明确的目标。具体目标1：确定A190是否抑制视网膜下NV。具体目标2： 确定A190是否抑制氧化应激/炎症。拟议中的研究将证明具有治疗作用 该化合物对AMD模型的影响，将为进一步的PK、毒性、机制研究奠定坚实的基础。 未来二期工程。

SUMMARY Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the U.S. Wet AMD accounts for up to 90% of vision loss in AMD patients, which is characterized by choroidal neovascularization (CNV). Currently, no cure exists for AMD, and available drug therapies focus on intravitreal injection of anti- vascular endothelial growth factor (VEGF) agents. These anti-VEGF drugs have achieved impressive therapeutic effects on CNV in approximately 70% of AMD patients; however, the other 30% of patients remain unresponsive to anti-VEGF therapies. AMD is a multi-factorial disease，therapies that only target a single molecule (such as VEGF) do not benefit for all patients with AMD. Therefore, the development of new drugs to target multiple pathogenic factors with a single compound, is an unmet clinical need. Peroxisome proliferator-activated receptor α (PPARα) is a widely expressed, ligand-activated transcriptional factor. Recent studies provide strong evidence supporting that PPARα agonist could suppress the vicious cycle of chronic inflammation in the RPE and retina, a key cause in the pathogenesis of AMD. In addition, clinical studies have demonstrated that oral treatment of fenofibrate (an agonist of PPARα) could significantly reduce the need of laser photocoagulation for retinal neovascularization by 37-40%. PPARα agonist inhibits neovascularization and overproduction of multiple inflammatory factors in AMD animal models. Meanwhile, as small molecules, PPARα agonists can penetrate through the blood-retinal barrier, making it a promising novel oral option for the prevention and treatment of AMD. However, fenofibrate’s low specificity, low potency, and dose-limiting toxicities make it a non-ideal treatment option for AMD. Recently, our team has independently designed, synthesized, and screened more than 200 new PPARα agonists, from which we identified a novel non-fibrate compound A190, with significantly improved potency and selectivity for PPARα agonism (EC50 = ∼37 nM). It activates PPARα and upregulates expression of PPARα target genes in retinal cells, and confers anti-angiogenic and anti-inflammatory, and neuroprotective effects superior to fenofibrate. It also reduces retinal inflammation and vascular leakage in AMD models. We will evaluate the effects of A190 on retinal NV and inflammation in AMD animal models. The project will be achieved by two specific aims. Specific Aim 1: Determine whether A190 suppresses subretinal NV. Specific Aim 2: Determine whether A190 inhibits oxidative stress/inflammation. The proposed studies will prove the therapeutic effect of this compound on AMD models and will lay a solid ground for further PK, toxicity, mechanism studies in future Phase II project.