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

预防和治疗糖尿病视网膜病变的新型小分子

基本信息

批准号：
10080648
负责人：
Yuhong Anna Wang
金额：
$ 27.13万
依托单位：
EXCITANT THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080648
关键词：
Adult Age Agonist Animal Model Animals Antidiabetic Drugs Apoptosis Biological Assay Blindness Blood Vessels Capillary Endothelial Cell Cells Clinical Clinical Trials Complications of Diabetes Mellitus Crystallization Data Development Diabetes Mellitus Diabetic Retinopathy Down-Regulation Drug Kinetics Drug Targeting Drug usage Exhibits Extravasation FDA approved Fenofibrate Fibrates Future Genes Human Immunohistochemistry In Situ Nick-End Labeling In Vitro Inflammation Inflammatory Intercellular adhesion molecule 1 Lasers Leukostasis Measures Modeling Muller&apos s cell Nerve Degeneration Neurons Oral Oral Administration Oxidative Stress PPAR alpha Parents Pathogenicity Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Processes Play Prevention Protein Isoforms Retina Retinal Degeneration Reverse Transcriptase Polymerase Chain Reaction Risk Role Small Business Innovation Research Grant Solid Specificity Streptozocin Structure TNF gene Therapeutic Therapeutic Effect Vascular Endothelial Growth Factors Vascular Permeabilities Vision Western Blotting base cell motility cell type design diabetes management diabetic diabetic patient diabetic rat drug candidate drug development experimental study improved intravitreal injection macular edema neovascularization neuron apoptosis neuroprotection novel novel therapeutics preclinical study programs prospective retinal neuron safety study small molecule three-dimensional modeling

项目摘要

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.

概括糖尿病视网膜病变（DR）是糖尿病的常见并发症，也是导致失明的主要原因目前，还没有任何非侵入性治疗方法能够完全缓解世界各地的工作年龄成年人的症状。因此，迫切需要一种长期预防和治疗的新药来改善DR进展。最近，两项独立的前瞻性临床试验（FIELD 和 ACCORD）已确定我们之前的实验表明，非诺贝特（一种 PPARα 激动剂）对 DR 具有前所未有的治疗效果。证实糖尿病引起的 PPARα 下调在 DR 中起关键致病作用，进一步表明 PPARα 是 DR 的一个有前途的药物靶标，然而，非诺贝特是一种低效 PPARα 激动剂，使其不是 DR 的理想治疗选择，并且尚未被 FDA 批准为抗 DR 药物。最近，我们团队开发了使用 PPARα 激动剂的新型口服药物是一个未满足的临床需求。自主设计、合成和筛选了200多种新型小分子化合物，使用 PPARα A190（EC50 = ∼27 nM）选择与非诺贝特不同的晶体结构。领先化合物，因为它具有显着的 PPAR α 激动剂特性，显示出更高的功效。 PPARα 激动作用（比其母体化合物 Y-0452 EC50 = ~50 µM 和非诺贝特高约 2700 倍）。重要的是，A190 还被证明在保护视网膜方面比非诺贝特更有效。这些研究结果表明 A190 是一种新型 PPARα 激动剂，具有较高的活性。该项目将作为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 是否减少糖尿病模型中的视网膜炎症和血管渗漏。 A190 是否可以保护糖尿病模型中的视网膜神经元该 SBIR 第一阶段项目将评估 A190 的效果。这种新型 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，为该候选药物的未来开发奠定坚实的基础，例如 II 期临床前研究中的药代动力学 (PK) 和安全性研究。