Low Molecular Weight Erythropoietin Mimetics For Improved CNS Penetrance And Trea

描述(申请人提供)：促红细胞生成素受体(EPOR)在中枢神经系统(CNS)中的表达的发现，导致了与促红细胞生成素(EPO)神经保护相关的研究激增，除了众所周知的造血特性。EPO通过抑制神经元和脑血管的凋亡等方式在中枢神经系统发挥神经保护作用，并通过促进血管生成和诱导红系细胞分化来改善组织氧合作用。重组人(Rh)促红细胞生成素的治疗还与缺血性中风患者的随访和预后评分的改善以及梗死面积缩小的强烈趋势有关。然而，重组人促红细胞生成素通过血脑屏障的能力有限，因此在中枢神经系统中的浓度远低于循环中的浓度。低分子量促红细胞生成素模拟物最近被描述为具有体外神经保护和体内造血活性，但为了获得最佳的体内神经保护效果，还需要改进中枢神经系统活性的效力、药代动力学和药物性质。该研究计划的目标是鉴定更多的小分子EPO模拟化合物，并对结构-活性关系进行初步分析。此外，本项目旨在分析这些化合物的神经保护活性和中枢神经系统通透性的药代动力学。总的目标是有朝一日开发这些治疗缺血性中风的化合物，因为重组人促红细胞生成素已经在这一适应症中证明了临床概念，而且与重组人促红细胞生成素的治疗相比，拟议的低分子促红细胞生成素模拟物的物理和功能特性的改善将为这些患者提供显著的好处。基于这种方法的新型EPO模拟物有望显示出改善的血脑屏障通透性，同时提供每日一次口服剂量的便利性和安全性，并缺乏免疫原性，这是与rhEPO相关的风险。中风是一种主要的未得到满足的医疗需求，仅在美国，中风造成的经济负担估计就高达数万亿美元。公共卫生相关性：拟议研究的目标是确定和表征类药物低分子促红细胞生成素模拟物，以提供治疗缺血性中风的候选新疗法。来自拟议研究的化合物有可能改进中风患者的治疗方法，以及当需要神经保护效果时对其他中枢神经系统疾病的治疗方法。

DESCRIPTION (provided by applicant): The discovery of the expression of erythropoietin receptor (EPOR) in the central nervous system (CNS) has led to a surge in research related to neuroprotection by erythropoietin (EPO), in addition to its well-known hematopoietic properties. EPO induces neuroprotective effects in the CNS through, for example, inhibition of apoptosis in neurons and cerebrovasculature, and it also improves tissue oxygenation through the promotion of angiogenesis and induction of erythroid cell differentiation. Treatment with recombinant human (rh) EPO was also associated with an improvement in follow-up and outcome scales and a strong trend for reduction in infarct size in patients with ischemic stroke. However, rhEPO has only limited ability to cross the blood-brain barrier (BBB), and therefore, the concentrations of rhEPO in the central nervous system are far lower than in circulation. Low molecular weight EPO mimetics were recently described with in vitro neuroprotective and in vivo hematopoietic activities, but improvements in potency, pharmacokinetics, and drug properties for CNS activity are required for optimal in vivo efficacy for neuroprotection. The objective of this research program is to identify additional small molecule EPO mimetic compounds and to perform initial analysis of structure-activity relationships. Moreover, this program aims to analyze these compounds for their neuroprotective activities and pharmacokinetics for CNS penetrance. The overall goal is to one day develop these compounds for ischemic stroke, because rhEPO has demonstrated clinical proof-of-concept in this indication, and the improved physical and functional properties of the proposed low molecular weight EPO mimetics would provide significant benefits for these patients when compared to treatment with rhEPO. Novel EPO mimetics from this approach are expected to demonstrate improved BBB permeability, while at the same time providing the convenience and safety of once-daily oral dosing and a lack of immunogenicity, a risk associated with rhEPO. Stroke represents a major unmet medical need and the economic burden of stroke in the United States alone has been estimated in the trillions of dollars. PUBLIC HEALTH RELEVANCE: The objective of the proposed studies is to identify and characterize drug-like low molecular weight erythropoietin mimetics to provide candidate new therapies for ischemic stroke. The compounds derived from the proposed studies have the potential to improve the therapeutic approaches in stroke patients, as well as in other diseases of the central nervous system when neuroprotective effects are desired.