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:7276709
- 负责人:
- 金额:$ 100.22万
- 依托单位:
- 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 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Brain InjuriesAnimal ModelAnimalsApoptosisAppendixBiological AssayBiological TestingBrain Hypoxia-IschemiaBrain InjuriesBrain IschemiaCaspaseCaspase InhibitorCell DeathCellsCellular biologyCerebral IschemiaChemicalsChemistryChronicClassClassificationClinicalClinical TrialsCollectionConditionDevelopmentDoseDrug FormulationsDrug KineticsGlucoseGoalsGuanosine MonophosphateHumanIn VitroInjuryInstitutesInvestigationIschemiaIschemic Brain InjuryLeadLethal Dose 50MetabolicMiddle Cerebral Artery OcclusionModelingMusNecrosisNeurodegenerative DisordersNeuronal InjuryNeuronsOxygenPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhasePhase I Clinical TrialsPhysiologicalPhysiologyPlayProcessRangeRattusResearch PersonnelRodent ModelRoleSafetyScreening procedureSeriesSolubilityStrokeSystemTestingTimeToxic effectToxicologyTraumaUnited States Food and Drug AdministrationWorkbaseconceptdeprivationhigh throughput screeningimprovedin vivoinhibitor/antagonistmouse modelneuron lossneurotoxicitynovelpre-clinicalprogramsscale upsmall 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):
这项建议的目的是开发能抑制坏死性下垂(一种程序性坏死)的坏死素,作为治疗急性脑损伤的新疗法。细胞凋亡在生理性神经细胞死亡中起重要作用,也是病理性神经细胞死亡的原因之一。然而,越来越多的证据表明,细胞具有另一种细胞死亡机制,当被激活时,这种机制会导致细胞死亡,并以坏死为特征,我们称之为“坏死性下垂”。从大约100,000个化合物中筛选出了九类结构不同的小分子坏死性下垂抑制剂,称为坏死抑素。初步的“概念验证”工作已经在体内证明了一种Necrostatin在延长时间窗内减少缺血性脑损伤的效果。计划通过再筛选100,000种化合物来扩大这一努力(具体目标1)。将通过icv递送的方式在体内分析原代神经元中针对缺氧和葡萄糖剥夺的保护以及在小鼠大脑中动脉闭塞模型中的死亡抑素池,以选择至少两种用于进一步优化的先导化合物(特定目标2)。将开展药物化学,以提高先导化合物的功效和生物利用度,并降低毒性(具体目标3)。将利用脑缺血损伤的啮齿动物模型和脑缺血损伤的大型动物模型(特定目标4),系统地分析铅化合物抑制急性脑损伤的效果。将对先导化合物系列进行药代动力学、ADME和毒理学分析。最后,将选择一种对大动物脑缺血有效且清洁安全的临床前候选药物进行临床开发。第一阶段研究的药物产品将在GMP条件下进行GLP分析,并将进行进一步的毒理学(GLP)和安全药理学研究(具体目标5)。该项目最终将向FDA提交IND申请,以进入第一阶段的人体临床试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JUNYING YUAN其他文献
JUNYING YUAN的其他文献
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{{ truncateString('JUNYING YUAN', 18)}}的其他基金
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- 资助金额:
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8729514 - 财政年份:2013
- 资助金额:
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8620945 - 财政年份:2013
- 资助金额:
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Investigating the mechanism of TNFalpha mediated cell death in oligodendrocytes
研究 TNFα 介导的少突胶质细胞死亡机制
- 批准号:
8851697 - 财政年份:2013
- 资助金额:
$ 100.22万 - 项目类别:
Investigating the mechanism of TNFalpha mediated cell death in oligodendrocytes
研究 TNFα 介导的少突胶质细胞死亡机制
- 批准号:
9084667 - 财政年份:2013
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$ 100.22万 - 项目类别:
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细胞坏死细胞死亡途径的分子机制
- 批准号:
7633055 - 财政年份:2009
- 资助金额:
$ 100.22万 - 项目类别:
A High Throughput Screen for Inhibitors of a Novel Necrotic Cell Death Pathway
新型坏死细胞死亡途径抑制剂的高通量筛选
- 批准号:
7304402 - 财政年份:2007
- 资助金额:
$ 100.22万 - 项目类别:
Development of Anti-necrosis Drug for Acute Brain Injury
急性脑损伤抗坏死药物的研制
- 批准号:
7100711 - 财政年份:2006
- 资助金额:
$ 100.22万 - 项目类别: