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：
7928155
负责人：
DAVID R SCHUBERT
金额：
$ 81.97万
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 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928155
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.

中风是全世界死亡的主要原因，其患病率随着寿命的延长和肥胖相关血管疾病的增加而增加。然而，有效的治疗方法很少。在过去的几年中，我们发现了一种对中风具有广泛神经保护作用的先导化合物，并合成了一系列分为两类的衍生物。一组具有 BDNF 样活性，并且在葡萄糖饥饿、氧化应激和营养因子撤退的细胞培养测定中具有活性。在某些检测中，最好的先导化合物的 EC50 低于 10 纳摩尔。另一组可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进行改进以降低其 EC50。两组化合物在体外缺血细胞培养模型中均具有活性。我们最初的线索之一可以增强啮齿类动物的记忆力，并且在兔子缺血模型中具有神经保护作用。该提案的目标是通过合成化学合成和改善两类药物的药理学特性，并确定它们的特定靶点和导致神经保护的分子途径。这些信息不仅有助于我们改进药物，而且还为确定药物开发新靶点提供了可能性。最后，这些化合物将被单独或组合地放入严格的兔缺血模型中，以确定它们的临床开发潜力。我们认为，在这项工作结束时，我们将鉴定出一类全新的神经保护化合物，了解它们的功能，并证明其针对中风的临床前开发的可行性。