Low Molecular Weight Erythropoietin Mimetics For Improved CNS Penetrance And Trea

描述（由申请人提供）：在中枢神经系统（CNS）中发现促红细胞生成素受体（EPOR）的表达，除了其众所周知的造血特性外，还导致了与促红细胞生成素（EPO）神经保护相关的研究激增。EPO通过抑制神经元和脑血管细胞凋亡等方式在中枢神经系统中诱导神经保护作用，并通过促进血管生成和诱导红细胞分化等方式改善组织氧合。重组人（rh） EPO治疗还与缺血性卒中患者随访和结局量表的改善以及梗死面积减小的强烈趋势相关。然而，rhEPO通过血脑屏障（BBB）的能力有限，因此，rhEPO在中枢神经系统中的浓度远低于循环中的浓度。低分子量EPO模拟物最近被描述为具有体外神经保护和体内造血活性，但为了达到最佳的体内神经保护效果，需要改进效力、药代动力学和药物特性。本研究计划的目的是鉴定额外的小分子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CNS外显率的药代动力学。总的目标是有一天开发出这些用于缺血性卒中的化合物，因为rhEPO在这一适应症中已经证明了临床概念验证，并且与rhEPO治疗相比，所提出的低分子量EPO模拟物的物理和功能特性的改善将为这些患者提供显着的益处。这种方法的新型EPO模拟物有望改善血脑屏障的通透性，同时提供每日一次口服给药的便利性和安全性，并且缺乏与rhEPO相关的免疫原性风险。中风代表了一个主要的未满足的医疗需求，仅在美国，中风的经济负担估计就高达数万亿美元。公共卫生相关性：拟议研究的目的是鉴定和表征药物样低分子量促红细胞生成素模拟物，为缺血性卒中提供候选新疗法。从提出的研究中得到的化合物有可能改善中风患者的治疗方法，以及当需要神经保护作用时，在其他中枢神经系统疾病中。

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.