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

摘要 糖尿病视网膜病变(DR)是糖尿病的常见并发症，也是致盲的主要原因 世界各地的劳动适龄成年人。目前，还没有一种非侵入性的治疗方法可以完全钝化。 进步博士。因此，迫切需要一种长效预防和治疗的新药来改善这种状况。 博士的管理最近，两项独立的前瞻性临床试验(FIELD和ACCORD)已经确定 非诺贝特(一种PPARα激动剂)对Dr具有前所未有的治疗效果 证实糖尿病诱导的PPARα下调在DR中起关键致病作用，进一步提示 然而，非诺贝特是一种低效的PPARα激动剂，它可以 这使得它不是治疗DR的理想选择，也没有被FDA批准为抗DR药物。因此， 使用PPARα激动剂开发新的口服药物是一个尚未满足的临床需求。最近，我们团队已经 自主设计、合成和筛选出200多种新型小分子化合物， 使用PPARα3D建模非诺贝特的不同晶体结构。选择A190(EC50=∼27 NM)作为 先导化合物，因为它具有显著的PPARα激动剂特性。A190显示出更好的性能 PPARα激动剂(约2700倍于其母化合物Y-0452EC_(50)=∼50µM和非诺贝特)。 重要的是，A190也被证明在保护视网膜方面可能比非诺贝特更有效 体外培养神经元和血管细胞。这些发现表明A190是一种新的PPARα激动剂，具有更高的 非诺贝特对糖尿病视网膜病变的治疗潜力。该项目将作为一项概念验证研究来调查 新型PPARα激动剂A190在糖尿病动物模型中的作用。该计划包括两个具体目标。 1：确定A190是否可以减少糖尿病模型中的视网膜炎症和血管渗漏。2：确定 A190是否保护糖尿病模型中的视网膜神经元。这项SBIR第一期项目将评估 新型PPARα激动剂A190对视网膜氧化应激、炎症、神经元凋亡和血管渗漏的影响 在糖尿病动物模型中，并为该候选药物的未来开发奠定了坚实的基础，例如 第二阶段临床前研究中的药代动力学(PK)和安全性研究。

SUMMARY Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness among working-age adults around the world. Currently, there is no non-invasive treatment demonstrated to fully blunt DR progression. Thus, a new drug for long-term prevention and treatment is urgently needed to improve the management for DR. Recently, two independent prospective clinical trials (FIELD and ACCORD) have identified that fenofibrate (a PPARα agonist) has unprecedented therapeutic effects in DR. Our previous experiment has confirmed PPARα down-regulation induced by diabetes plays a key pathogenic role in DR, further suggesting that PPARα is a promising drug target for DR. However, fenofibrates is a low potency PPARα agonist, which makes it not an ideal treatment option for DR and has not been approved as an anti-DR drug by FDA. Therefore, the development of novel oral drugs using PPARα agonists is an unmet clinical need. Recently, our team has independently designed, synthesized and screened more than 200 novel small molecule compounds, with different crystal structures from fenofibrate using PPARα 3D modeling. A190(EC50 = ∼27 nM) is selected as the leader compound since it possesses significant PPAR α agonist feature. A190 exhibited improved potency for PPARα agonism (~2700 fold higher than its parent compound Y-0452 EC50 = ∼50 µM and fenofibrate). Importantly, A190 has also proven to be potentially more effective than fenofibrate in the protection of retinal neurons and vascular cells in vitro. These findings suggest that A190 is a novel PPARα agonist with higher therapeutic potential for DR than fenofibrate. This project will serve as a proof-of-concept study to investigate the effects of the novel PPARα agonist A190 in a diabetic animal model. The program includes two specific aims. 1: Determine whether A190 reduces retinal inflammation and vascular leakage in a diabetic model. 2: Determine whether A190 protects retinal neurons in a diabetic model. This SBIR Phase I project will evaluate the effect of this novel PPARα agonist A190 on retinal oxidative stress, inflammation, neuron apoptosis and vascular leakage in a diabetic animal model, and lay a solid groundwork for future development of this drug candidate, such as pharmacokinetic (PK) and safety studies, in the Phase II preclinical studies.