A Novel Family of Neuroprotective Compounds for Stroke

治疗中风的新型神经保护化合物家族

基本信息

批准号：
7655854
负责人：
DAVID R SCHUBERT
金额：
$ 81.73万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7655854
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Affinity Chromatography Age Amyloid Animal Model Animals Antioxidants Apoptosis Binding Sites Biological Assay Brain-Derived Neurotrophic Factor Cause of Death Cell Culture Techniques Cell Death Characteristics Clinic Clinical Collaborations Curcumin Development Disease Enzymes Family Gel Gene Expression Profiling Glucose Glutamates Goals Growth Factor In Vitro Individual Ischemia Laboratories Lead Libraries Longevity Memory Modeling Molecular Molecular Target Molecular Weight Nervous System Trauma Neurons Neuroprotective Agents Obesity Older Population Oryctolagus cuniculus Oxidative Stress Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphoproteins Phosphorylation Phosphotransferases Prevalence Property Protein Kinase Proteins Public Health Purines Rattus Reagent Risk Factors Rodent Screening procedure Series Signal Pathway Signal Transduction Specificity Starvation Stroke Structure Synthesis Chemistry Testing Therapeutic Toxic effect Vascular Diseases Withdrawal Work analog base bisphenol A combinatorial combinatorial chemistry design disability drug development excitotoxicity falls hydroxyl group improved in vitro Model inhibitor/antagonist member neuroprotection novel pharmacophore pre-clinical prevent purine response small molecule

项目摘要

Stroke is a major cause of death throughout the world and its prevalence is increasing with increased longevity and obesity-associated vascular disease. There are, however, very few effective therapeutics. During the last few years we have identified a broadly neuroprotective lead compound for stroke and have synthesized a series of derivatives that fall into two classes. One group has BDNF-like activity and is active in cell culture assays for glucose starvation, oxidative stress, and trophic factor withdrawal. The best lead has an EC50 in some of these assays below 10 nanomolar. The other group inhibits glutamate-induced excitotoxicity, but needs to be improved via combinatorial and medicinal chemistry to lower its EC50. Both groups of compounds are active in cell culture models of in vitro ischemia. One of our initial leads enhances memory in rodents and is neuroprotective in a rabbit ischemia model. It is the goal of this proposal to synthesize and improve the pharmacological properties of both classes of drugs through synthetic chemistry and to identify their specific targets and molecular pathways that lead to neuroprotection. This information will not only help us improve our drugs but also open the possibility of identifying new targets for drug development. Finally, these compounds will be put into a rigorous rabbit ischemia model both individually and in combination to determine their potential for clinical development. We feel that at the end of this work we will have identified a completely new class of neuroprotective compounds, understand how they function, and demonstrated the feasibility for their pre-clinical development for stroke.

中风是全世界的主要死亡原因，随着寿命和肥胖相关的血管疾病的增加，其流行率正在增加。但是，很少有有效的治疗学。在过去的几年中，我们已经确定了中风广泛的神经保护铅化合物，并合成了一系列属于两个类别的衍生物。一组具有类似BDNF的活性，并且在细胞培养测定中活跃于葡萄糖饥饿，氧化应激和营养因子戒断。最好的铅在低于10纳摩尔的某些测定中具有EC50。另一组抑制谷氨酸诱导的兴奋性毒性，但需要通过组合和药物化学改善以降低其EC50。两组化合物在体外缺血的细胞培养模型中均活跃。我们的初始铅之一可增强啮齿动物的记忆，并在兔缺血模型中具有神经保护作用。该建议的目的是通过合成化学合成和改善两类药物的药理特性，并确定其特定靶标和分子途径，从而导致神经保护作用。这些信息不仅将帮助我们改善药物，而且还可以开放确定新目标的药物开发目标。最后，这些化合物将分别和结合使用，以确定它们的临床发育潜力。我们认为，在这项工作结束时，我们将确定一类全新的神经保护化合物，了解它们的功能，并证明其对中风前临床前发展的可行性。