Hit to Lead Optimization of a Systemically Available Treatment for Diabetic Retinopathy

项目摘要。自1980年以来，糖尿病的患病率几乎翻了一番。当前人口 增长率和老龄化人口结构预测糖尿病和相关疾病的负担将更快地上升 未来几年的复杂情况。糖尿病视网膜病变(DR)影响约30%的糖尿病患者，代表 在工业化国家和发展中国家，工人阶级失明的主要原因。尽管有一系列 治疗方案(即激光光凝、血糖调节、皮质类固醇和抗血管药物 血管内皮细胞生长因子(VEGF)注射)，解决DR复杂性的能力仍然是一个重要的 挑战。手术方法具有不可逆转的破坏性，护理标准(即抗血管内皮生长因子治疗)受到影响 由于需要频繁注射，费用高昂(2008-09年度为15亿美元)，发展中国家获得的机会有限， 并且必须由医疗专家进行管理。因此，存在着对低成本、现成的迫切需求 可获得的、系统可用的DR治疗。尤其重要的是治疗方法的发展 这同时解决了参与DR病因学的炎症和新生血管(NV)事件。 PPARα激动剂已被证明是一种在治疗上可行的选择，以解决主要的病理 糖尿病黄斑水肿的特征导致DR视力丧失到目前为止，非诺贝特是唯一的PPARα 已知的一种激动剂，能穿过血眼屏障，对DME和NV具有保护作用。非诺贝特 然而，PPAR家族的不同成员之间缺乏选择性， 和剂量限制毒性，这将限制其作为DR治疗的使用。然而，非诺贝特的结果表明， 显示出增强效力和增强眼球分布的PPARα激动剂具有很高的前景 成为一种低成本和口服治疗DR的选择最近，NCI8被发现 作为一种新型的PPARα激动剂，该化合物表现出等效性和等效性 非诺贝特的体内外疗效比较。然而，与非诺贝特不同，nci8是一种选择性的pparα。 激动剂，因此我们假设这种化学型可以被合理地优化为一种有效的有效的 针对DR的小分子治疗本方案的目的是进行迭代结构活性 关系研究，以优化NCI8从命中到可行的治疗线索。这项提案的目的将是 并行进行，包括1)合理设计的受NCI8启发的衍生物的合成和2) 在最初的体外和体内试验中，评估新的衍生物作为PPARα激动剂的作用。寻求治疗 具有系统可用小分子的DR是创新的，因为它偏离了所有已知的当前治疗方法 选择。这项研究具有重要意义，因为IS寻求提供一种广泛可用的DR治疗方案，以解决 当前护理标准带来的成本、可获得性和管理限制。

Project Summary. The prevalence of diabetes mellitus (DM) has nearly doubled since 1980. Current population growth rates and aging demographics predict an even more rapid rise in the burden of DM and associated complications in the years to come. Diabetic retinopathy (DR) affects ~30% of diabetics and represents the leading cause of working class blindness in both the industrialized and developing nations. Despite a range of treatment options (i.e. laser photocoagulation, blood-glucose regulation, corticosteroids and anti-vascular endothelial growth factor (VEGF) injections), the ability to address the complex nature of DR remains a significant challenge. Surgical methods are irreversibly destructive and the standard of care (i.e. anti-VEGF therapy) suffers from the requirement of frequent injections, high cost ($1.5 B in 2008-09), limited access in developing countries, and must be administered by healthcare specialists. Therefore, a critical need exists for low-cost, readily accessible, and systemically available DR treatments. Of particular importance is the development of therapies that simultaneously address the inflammatory and neovascularization (NV) events involved in DR etiology. PPARα agonism has demonstrated promise as a therapeutically viable option to address the major pathological features of diabetic macular edema responsible for vision loss in DR. To date, fenofibrate is the only PPARα agonist known to cross the blood-ocular barrier and provide protective effects against DME and NV. Fenofibrate however, suffers from low ocular distribution, lack of selectivity between different members of the PPAR family, and dose limiting toxicity, which will limit its use as a DR therapy. The fenofibrate results, however, demonstrate that PPARα agonists that exhibit improved potency and enhanced ocular distribution have high promise to become a low-cost and orally available therapeutic option for the treatment of DR. Recently, NCI8 was identified from a computational screen as a novel PPARα agonist and this compound exhibits equipotency and equal efficacy to fenofibrate in vitro and in vivo, respectively. Unlike fenofibrate, however, NCI8 is a selective PPARα agonist and thus we hypothesize that this chemotype can be rationally optimized into a potent and efficacious small molecule treatment for DR. The objective of this proposal is to conduct iterative structure-activity relationship studies to optimize NCI8 from a hit into viable therapeutic leads. The aims of this proposal will be conducted in parallel and include 1) the synthesis of rationally designed NCI8-inspired derivatives and 2) the assessment of the new derivatives to act as PPARα agonists in initial in vitro and in vivo assays. Seeking to treat DR with a systemically available small molecule is innovative, as it deviates from all known current therapeutic options. This research is significant as is seeks to provide a widely available DR treatment option that addresses the cost, availability, and administration limitations posed by the current standard of care.