权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of Anti-necrosis Drug for Acute Brain Injury

急性脑损伤抗坏死药物的研制

基本信息

批准号：
7495127
负责人：
JUNYING YUAN
金额：
$ 25.7万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495127
关键词：
Acute Acute Brain Injuries Animal Model Animals Apoptosis Appendix Biological Assay Biological Testing Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia Caspase Caspase Inhibitor Cell Death Cells Cellular biology Cerebral Ischemia Chemicals Chemistry Chronic Class Classification Clinical Clinical Trials Collection Condition Development Dose Drug Formulations Drug Kinetics Glucose Goals Guanosine Monophosphate Human In Vitro Injury Institutes Investigation Ischemia Ischemic Brain Injury Lead Lethal Dose 50 Metabolic Middle Cerebral Artery Occlusion Modeling Mus Necrosis Neurodegenerative Disorders Neuronal Injury Neurons Oxygen Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Physiological Physiology Play Process Range Rattus Research Personnel Rodent Model Role Safety Screening procedure Series Solubility Stroke System Testing Time Toxic effect Toxicology Trauma United States Food and Drug Administration Work base concept deprivation high throughput screening improved in vivo inhibitor/antagonist mouse model neuron loss neurotoxicity novel pre-clinical programs scale up small molecule

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to develop necrostatins that inhibit necroptosis, a type of programmed necrosis, as a novel therapy for acute brain injury. Apoptosis plays a critical role in physiological neuronal cell death and also contributes to pathological neuronal cell death. However, evidence is accumulating that cells possess an alternative mechanism of cell death which when activated induces cell death with features of necrosis which we termed "necroptosis". Nine structurally distinct classes of small molecule inhibitors of necroptosis, termed necrostatins, have been identified from screening approximately 100,000 compounds. Preliminary "proof-of-concept" work has demonstrated in vivo efficacy of a necrostatin in reducing ischemic brain injury with a prolonged time window. The plan is to expand this effort by screening an additional 100,000 compounds (Specific Aim 1). The pool of necrostatins will be analyzed in primary neurons for protection against oxygen and glucose deprivation and in mouse model of middle cerebral artery occlusion in vivo by icv delivery to select at least two lead compounds for further optimization (Specific Aim 2). Medicinal chemistry will be carried out to improve the efficacy and bio-availability of the lead compounds and to reduce toxicity (Specific Aim 3). The efficacy of lead compounds in inhibiting acute brain injury will be analyzed systematically using rodent models of ischemic brain injury and in a large animal model of ischemic brain injury (Specific Aim 4). The lead compound series will be analyzed for their pharmacokinetic, ADME and toxicology profiles. Finally, a pre-clinical candidate with efficacy in cerebral ischemia in a large animal and clean safety pharmacology will be selected for clinical development. Drug product for a Phase 1 study will be manufactured under GMP conditions with GLP analytics, and further toxicology (GLP) and safety pharmacology studies will be conducted (Specific Aim 5). This project will culminate with the filing of an IND application with the FDA in order to enter a Phase I human clinical trial.

描述（由申请人提供）：