Novel, Orally-Available Prodrugs for Alzheimer's Disease

治疗阿尔茨海默病的新型口服前药

基本信息

批准号：
9407923
负责人：
Francis X Tavares
金额：
$ 98.35万
依托单位：
RESILIO THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407923
关键词：
Academic Medical Centers Adsorption Adverse effects Affect African Trypanosomiasis Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model American Amino Acids Amyloid beta-Protein Animals Anti-Inflammatory Agents Anti-inflammatory Arginine Autopsy Behavior Bioavailable Biological Biological Availability Biological Response Modifiers Blood Blood - brain barrier anatomy Brain Brain Diseases Catabolism Cells Characteristics Cleaved cell Clinical Trials Cognitive Complex Critical Pathways DL-alpha-Difluoromethylornithine Dementia Development Disease Disease Progression Dose Drug Kinetics Drug Targeting Eflornithine Eligibility Determination Environment Enzymes Europe FDA approved Formulation Future Gene Expression Generations Half-Life Heart Human Huntington Disease Immune Immunosuppression Immunosuppressive Agents In Vitro Inflammatory Intravenous Investments Laboratories Lead Learning Legal patent Lung Malignant Neoplasms Measures Mediator of activation protein Memory Metabolism Methods Modeling Monkeys Movement Mus Mutagenicity Tests Oral Oral Administration Ornithine Ornithine Decarboxylase Parasitic infection Parkinson Disease Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase Plasma Polyamines Population Prevalence Problem Solving Prodrugs Progress Reports Publications Publishing Putrescine Rattus Reporting Safety Senile Plaques Small Business Innovation Research Grant Spermine Synthase Symptoms Testing Therapeutic Therapeutic Equivalency Time Toxic effect Transferase Treatment Efficacy Writing analog arginase base clinical development commercialization cost design drug market esterase immunotoxicity improved in vitro activity in vivo inhibitor/antagonist mouse model novel novel strategies response safety testing scale up

项目摘要

Project Summary for Novel, Orally-available Prodrugs for Alzheimer's Disease Dr. Colton at Duke University Medical Center was among the first to publish that early stages of Alzheimer's disease were characterized by an immuno-suppressive condition in the brain (Colton et al. 2006a). As the disease progresses, an immuno-toxic condition is acquired with disease progression so that at post- mortem analysis, both pro-inflammatory and anti-inflammatory immune mediators are present. In an elegant reduction to practice, Kan et al. (2015) used difluoromethylornithine (DFMO) to show that reduction of immuno- suppressive polyamines resulted in significantly improved learning and memory behavior and reduced Abeta 1- 40 and 1-42 in the CVN-AD mouse model of AD. Town's laboratory (Guillot-Sestier et al. 2015) and Chakrabaty et al. (2015) showed that increasing immuno-suppressive activities was associated with enhanced amyloid plaque formation and worsening cognitive behavior, while removing immuno-suppressive activities appears to mitigate these Alzheimer's-like pathologies. These and other publications provide strong support for the idea that reducing immuno-suppression may be a new and effective therapeutic approach to Alzheimer's disease reduction. Polyamines are immuno-suppressive mediators and polyamine levels increase in AD brains. DFMO is a potent, orally-available irreversible inhibitor of the key enzyme required for polyamine synthesis, Ornithine DeCarboxylase (ODC). Thus, our treatment thesis is to reduce brain polyamine levels to reduce brain immuno-suppression and inhibit and/or stop the development of disease when treatment is initiated at early stages of AD. DFMO is an FDA-approved drug for the treatment of sleeping sickness due to parasitic infection of the brain that is off-patent and no longer marketed, making commercialization a challenge. We have solved this problem by creating novel prodrugs of DFMO that reduce polyamine levels, are orally-available, may not have the same undesirable side-effect profile as DFMO-alone, and are patent-pending (Tavares and Vitek, WO 2016/168118 A1). In Phase 1, we successfully created DFMO-prodrugs and characterized them in vitro. In Phase 2, we are proposing to continue development of DFMO-prodrugs by making additional prodrugs, characterizing them in vitro and in vivo, determining whole animal pharmacokinetic and pharmacodynamic profiles, and testing them in the CVN-AD mouse model. These additional activites are laying the groundwork for selection of a lead and a backup compound, an important milestone on the critical-path that will be taken into clinical development of Resilio's DFMO-prodrugs for an Alzheimer's indication.

阿尔茨海默病新型口服前药项目摘要杜克大学医学中心的科尔顿博士是最早发表早期阶段研究的人之一阿尔茨海默氏病的特点是大脑中的免疫抑制状况（Colton 等人，2006a）。随着疾病的进展，免疫毒性病症会随着疾病的进展而出现，因此在治疗后尸检分析显示，存在促炎和抗炎免疫介质。在优雅的减少实践，Kan 等人。 (2015) 使用二氟甲基鸟氨酸 (DFMO) 表明，免疫- 抑制性多胺可显着改善学习和记忆行为并降低 Abeta 1- AD的CVN-AD小鼠模型中的40和1-42。 Town 的实验室（Guillot-Sestier 等人，2015）和查克拉巴蒂等人。（2015）表明，免疫抑制活性的增加与增强的免疫抑制活性相关。淀粉样斑块形成和认知行为恶化，同时消除免疫抑制活性似乎可以减轻这些类似阿尔茨海默病的病症。这些和其他出版物提供了强有力的支持认为减少免疫抑制可能是一种新的、有效的治疗方法减少阿尔茨海默病。多胺是免疫抑制介质，AD 大脑中多胺水平升高。 DFMO 是一种有效的口服不可逆抑制剂，多胺合成所需的关键酶鸟氨酸脱羧酶（ODC）。因此，我们的治疗论文是降低大脑多胺水平，以减少大脑早期开始治疗时，可发挥免疫抑制作用并抑制和/或阻止疾病的发展 AD 的阶段。 DFMO是FDA批准的药物，用于治疗寄生虫感染引起的昏睡病大脑的专利已经过期并且不再上市，这使得商业化成为一个挑战。我们已经解决了通过创造新的 DFMO 前药来解决这个问题，可以降低多胺水平，可以口服，但可能不会与单独使用 DFMO 具有相同的不良副作用，并且正在申请专利（Tavares 和 Vitek， WO 2016/168118 A1)。在第一阶段，我们成功创建了 DFMO 前药并在体外对其进行了表征。在第二阶段，我们建议通过制造额外的前药来继续开发 DFMO 前药，对其进行体外和体内表征，确定整个动物的药代动力学和药效学配置文件，并在 CVN-AD 小鼠模型中对其进行测试。这些额外的活动正在奠定基础对于选择先导化合物和备用化合物，将采取的关键路径上的一个重要里程碑 Resilio 的 DFMO 前药用于阿尔茨海默病适应症的临床开发。