嘧啶酮类Lp-PLA2抑制剂：结构优化及其治疗糖尿病性视网膜病变的初步评价

Diabetic retinopathy (DR) is a hyperglycemia-induced eye disease characterized by fundus damage and vision impairment. Although being ocular manifestation, DR is in its essence a systemic disease. The pathogenesis of DR is derived from impaired endothelial function and excessive inflammation in the retinal capillary caused by long-term duration of hyperglycemia. Current therapeutic drugs which act directly on the local lesion via intravitreal injection are quite inconvenient and accompanied with severe side effects. In view of this, it may be a feasible new treatment of DR by using a systemic agent that is able to improve the endothelial function of retinal capillary. Lipoprotein associated phospholipase A2 (Lp-PLA2) is tightly associated with DR for its capability of hydrolyzing ox-LDL to release pro-inflammatory mediators which have been demonstrated to cause vascular endothelial dysfunction. Darapladib, an orally active Lp-PLA2 inhibitor, delivered significant improvements to the symptoms of DR in a phase II clinical trial. However, Darapladib suffers from poor pharmacokinetic profiles. We have focused on exploring novel Lp-PLA2 inhibitors with better drug-like properties for several years. Most recently, we identified a couple of pyrimidone compounds with low molecular weight, moderate lipophilicity, high potency in vitro and synthetic accessibility. In this project, we will carry out systemic structural optimizations on this pyrimidone scaffold with the purpose of further improving the pharmacokinetic properties, and inhibitory activities both in vitro and in vivo. To determine if Lp-PLA2 could act as a potential systemic anti-DR target, one or two candidate compounds will be evaluated in rat model for their long term effects in the treatment of DR. The implementation of this project would help to lay foundation for the development of novel therapeutic approach for treating diabetic retinopathy.

糖尿病性视网膜病变（DR）是由高血糖引起的眼底损伤和视力障碍。DR虽然表现为眼部症状，但本质上是系统疾病，根源在于高血糖侵蚀视网膜微血管引起的内皮功能损伤和炎症反应。现有药物通过玻璃体注射作用于局部病灶，弊端明显，而应用系统性药物来改善内皮功能或许是一条可行的新治疗思路。脂蛋白相关的磷脂酶A2（Lp-PLA2）因能够水解ox-LDL，释放促炎症介质，引发血管内皮损伤而与DR联系在一起。口服Lp-PLA2抑制剂Darapladib在II期临床试验中对DR的疗效显著，但药代动力学性质较差。近期我们发现了类药性更好的Lp-PLA2抑制剂——分子量低、亲脂性适宜、体外活性高且易于合成的嘧啶酮类化合物。本项目将通过结构优化进一步改善这类化合物的药代动力学性质、提高体内外活性，用大鼠模型评价候选化合物对DR的治疗效果，以检验Lp-PLA2作为系统性抗DR靶点的潜力，为研究新的治疗策略奠定基础。

作为最常见的糖尿病并发症之一，糖尿病视网膜病变能够造成视力减退，是成人致盲的主要原因。目前该病主要的治疗手段包括激光光凝术和玻璃体内抗VEGF药物，但它们疗效有限且副作用显著，病人治疗的依从性差。Lp-PLA2抑制剂作为一种新的治疗糖尿病视网膜病变的策略已在临床试验中获得初步的概念验证，但该靶点的首创药物darapladib存在着药代动力学性质差、口服活性一般等缺点。本项目拟对前期工作中发现的嘧啶酮类化合物进行结构优化，以期获得改进型的Lp-PLA2抑制剂，并在动物模型上验证其治疗糖尿病视网膜病变的效果。在本项目中，我们不仅注重化合物活性的提高，也注重早期药物代谢性质和安全性的优化。我们按照“从体外评价到体内评价”的研究方案，逐级筛选优选化合物，以高效的方式获得了候选药物VO1和VP3。相比于darapladib，它们具备更合理的药代动力学性质、更强的口服活性和更好的安全性。此外，我们还应用基于片断的药物设计方法发现了一类苯磺胺类Lp-PLA2抑制剂，通过晶体结构的解析阐明了药物与Lp-PLA2的结合模式。在药效学研究中，我们应用多种动物模型和实验技术证明了VO1、VP3对改善糖尿病引起的视网膜损伤具有明确作用，且其药效优于darapladib。该研究结果进一步支持了将Lp-PLA2作为治疗糖尿病视网膜病变的有效靶点这一概念，同时也为基于该靶点研制更理想的药物奠定了基础。通过本项目的实施，我们发表了高质量论文2篇、获得授权专利3项、培养博士研究生1名。本项目发现的Lp-PLA2抑制剂拥有更好的成药性、拥有知识产权保护，展现了进一步开发的价值。