Mitochondrial Antioxidant Neurodegenerative Therapeutics: XJB-5-131 Derivatives

线粒体抗氧化神经退行性治疗：XJB-5-131 衍生物

基本信息

批准号：
8713803
负责人：
Janet Leeds
金额：
$ 22.6万
依托单位：
SOLANO PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8713803
关键词：
Acute Adult Adverse effects Alkenes Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Animals Antibiotics Antioxidants Biological Biological Availability Blood - brain barrier anatomy Body Weight decreased Cells Chemicals Clinical Clinical Trials D-Phe-Pro DNA Development Disease Dose Drug Interactions Drug Kinetics Enzymes Evaluation Event Failure Generic Drugs Goals Gramicidin Gramicidin S Half-Life Human Huntington Disease Impaired cognition In Vitro Injury Intestines Lead Liver Maximum Tolerated Dose Mediating Medical Membrane Proteins Metabolism Mitochondria Mitochondrial DNA Modeling Modification Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Oral Parents Parkinson Disease Pathogenesis Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Phase Property Reactive Oxygen Species Rodent Rodent Model Route Series Site Small Business Technology Transfer Research Solubility Source Specificity Testing Therapeutic Tissues Toxic effect Trauma United States age related analog base burden of illness design efficacy testing improved improved functioning in vivo intervertebral disk degeneration meetings mimetics mitochondrial membrane motor function improvement mouse model neuronal survival oxidation oxidative damage piperidine pre-clinical prevent public health relevance radiation effect research study scaffold scale up success

项目摘要

DESCRIPTION (provided by applicant): Oxidative damage to mitochondrial is a major source of toxicity in diseases such as Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD). Mitochondria are energy "powerhouses" of the cell, and decline in their function by oxidative damage is a common feature among neurodegenerative diseases. Despite years of effort, however, generic antioxidants have failed in clinical trials, and there are no effective therapeutics to offset the motor and cognitive decline in afflicted patients. The goal of this STTR application is to fill this medical gap. We have created a paradigm-shifting synthetic platform, in which antioxidants are targeted directly to MT, and reduce oxidative damage to their membranes, proteins, and DNA. The lead compound for this new platform is XJB-5-131, a synthetic, bi-functional molecule harboring a vehicle and a cargo. The cargo is the antioxidant portion, which neutralizes oxidative damage. The vehicle is a peptide mimetic that targets the antioxidant moiety directly to the mitochondrial membrane. XJB-5-131, crosses the blood-brain barrier, concentrates 600-fold in the MT, reduces oxidative damage in MT, improves motor function, prevents weight loss, and improves mitochondrial function in a mouse model of HD. These properties of synthetic XJB-5-131 overcome many sources of past failures, and render antioxidants a viable therapeutic strategy. Solano Pharmaceuticals will develop a series of analogues based on the lead compound, XJB-5- 131, which will be optimized for development as a clinical candidate. In Phase 1, we will identify the liabilities of the lead compound and efficacy facets of the molecule that need optimization. In Phase 2, we will focus on synthesis of molecules that improve the druglike properties of XJB-5-131. Successful analogues will be tested for efficacy in rodent models of HD and AD. The compounds that meet the required criteria will be moved into IND-enabling studies. AD alone is the largest growing burden of diseases in the United States, with nearly 6 million adults currently afflicted. Any viable therapeutic strategy would be a breakthrough with high clinical value.

描述（由申请人提供）：线粒体的氧化损害是阿尔茨海默氏症（AD），帕金森氏症（PD）和亨廷顿疾病（HD）等疾病中毒性的主要来源。线粒体是细胞的能量“动力室”，其功能通过氧化损伤下降是神经退行性疾病中的常见特征。然而，尽管经过多年的努力，临床试验中的通用抗氧化剂仍失败了，并且没有有效的治疗剂可以抵消患者患者的运动和认知能力下降。这个sttr的目标申请是填补此医疗空白。我们创建了一个范式移动合成平台，哪种抗氧化剂直接靶向MT，并减少对其膜，蛋白质和DNA的氧化损伤。这个新平台的铅化合物是XJB-5-131，这是一种携带车辆和货物的合成，双功能分子。货物是抗氧化剂部分，它中和氧化损伤。该媒介物是一种肽模拟物，将抗氧化部分靶向直接靶向线粒体膜。 XJB-5-131穿过血脑屏障，在MT中浓缩600倍，减少MT中的氧化损伤，改善运动功能，防止体重减轻并改善HD小鼠模型中的线粒体功能。合成XJB-5-131的这些特性克服了过去失败的许多来源，并使抗氧化剂成为可行的治疗策略。 Solano Pharmaceuticals将基于铅化合物XJB-5-131开发一系列类似物，该化合物将作为临床候选者进行优化。在第1阶段，我们将确定需要优化的分子的铅化合物和功效方面的负债。在第2阶段，我们将重点关注改善XJB-5-131药物样性能的分子的合成。成功的类似物将在HD和AD的啮齿动物模型中测试功效。符合所需标准的化合物将转移到辅助研究中。仅广告是美国最大的疾病增长负担，目前有近600万成年人受苦。任何可行的治疗策略都将是具有较高临床价值的突破。