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

项目摘要。自1980年以来，糖尿病（DM）的患病率几乎翻了一番。目前人口 增长率和人口老龄化预测糖尿病和相关疾病的负担会更快地上升， 并发症在未来几年。糖尿病视网膜病变（DR）影响约30%的糖尿病患者， 这是工业化国家和发展中国家工人阶级失明的主要原因。尽管有一系列的 治疗选择（即激光光凝、血糖调节、皮质类固醇和抗血管 血管内皮生长因子（VEGF）注射），解决DR的复杂性的能力仍然是一个重要的问题。 挑战.手术方法是不可逆的破坏性的，并且护理标准（即抗VEGF疗法）受到 由于需要频繁注射，成本高（2008-09年为15 B美元），在发展中国家获得的机会有限， 并且必须由医疗保健专家进行管理。因此，迫切需要低成本的、容易的 可获得的和全身可用的DR治疗。特别重要的是治疗方法的发展 同时解决DR病因学中涉及的炎症和新生血管形成（NV）事件。 PPARα激动剂已被证明是治疗上可行的选择，以解决主要的病理性 糖尿病性黄斑水肿是DR患者视力丧失的原因。迄今为止，非诺贝特是唯一一种 激动剂，已知可穿过血眼屏障，并提供对DME和NV的保护作用。非诺贝特 然而，其眼部分布低，在PPAR家族的不同成员之间缺乏选择性， 和剂量限制性毒性，这将限制其作为DR治疗的用途。然而，非诺贝特的结果表明， 显示出改善的效力和增强的眼部分布的PPARα激动剂具有很高的前景， 成为治疗DR的低成本和口服有效的治疗选择。最近，NCI 8被确定为 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。 分别在体外和体内对非诺贝特的功效。然而，与非诺贝特不同，NCI 8是一种选择性的PPARα， 因此，我们假设这种化学型可以合理地优化成一种有效的， 本提案的目的是进行迭代的结构-活性 关系研究，以优化NCI 8从命中到可行的治疗线索。这项建议的目的是 平行进行，包括1）合理设计的NCI 8衍生物的合成和2） 在初始体外和体内试验中评估新衍生物作为PPARα激动剂的作用。寻求治疗 具有全身可用的小分子的DR是创新的，因为它偏离了所有已知的当前治疗方法。 选项.这项研究意义重大，因为它旨在提供一种广泛可用的DR治疗方案， 当前标准治疗的成本、可用性和管理限制。

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.