A Novel Family of Neuroprotective Compounds for Stroke

治疗中风的新型神经保护化合物家族

• 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
• 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

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，其患病率随着寿命的延长和肥胖相关的血管疾病而增加。然而，有效的治疗方法很少。在过去的几年里，我们已经确定了一个广泛的神经保护性的铅化合物中风，并合成了一系列的衍生物，分为两类。一组具有BDNF样活性，并在葡萄糖饥饿、氧化应激和营养因子戒断的细胞培养试验中具有活性。最好的铅在这些测定中的一些中具有低于10纳摩尔的EC 50。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来改善以降低其EC50。两组化合物在体外缺血的细胞培养模型中均具有活性。我们最初的一种先导化合物增强了啮齿动物的记忆力，并在兔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这两类药物的药理学性质，并确定其导致神经保护的特定靶标和分子途径。这些信息不仅可以帮助我们改进药物，还可以为药物开发提供新的靶点。最后，将这些化合物单独和组合放入严格的兔缺血模型中，以确定其临床开发的潜力。我们认为，在这项工作结束时，我们将确定一种全新的神经保护化合物，了解它们的功能，并证明其用于中风临床前开发的可行性。