High throughput in vivo screening: translational generation of novel analgesics

高通量体内筛选：新型镇痛药的转化生成

基本信息

批准号：
8087405
负责人：
Richard Allen Houghten
金额：
$ 40.8万
依托单位：
TORREY PINES INST FOR MOLECULAR STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8087405
关键词：
Acute Address Adverse effects Agonist Analgesics Animal Model Animal Testing Area Biological Biological Assay Biological Sciences Chemicals Clinical Clinical Trials Complement Constipation Cyclic AMP Data Development Dose Drug Addiction Drug abuse Evaluation Exhibits Fostering Gastrointestinal Transit Generations Goals Housing Human In Vitro Individual Lead Libraries Life Marketing Measures Methodology Methods Mission Narcotic Antagonists National Institute of Drug Abuse National Institute of Mental Health Nociception Opioid Opioid Analgesics Pain Pathway interactions Patients Pharmaceutical Chemistry Pharmacologic Substance Positioning Attribute Preclinical Drug Evaluation Principal Investigator Process Property Psychotropic Drugs Quality of life Research Research Design Respiration Route Safety Scanning Science Screening procedure Solubility Staging Tail Techniques Testing Therapeutic Time Ursidae Family Ventilatory Depression Water Withdrawal Work addiction base combinatorial drug discovery high throughput screening improved in vitro Assay in vitro activity in vitro testing in vivo in vivo Model inflammatory neuropathic pain innovation interest mouse model nonmedical use novel pre-clinical preclinical study preference psychologic receptor internalization respiratory response scaffold small molecule small molecule libraries translational approach

项目摘要

DESCRIPTION (provided by applicant): The central working hypothesis of the proposed study is that the direct in vivo high throughput screening (in vivo HTS) will yield enhanced leads, thereby accelerating the discovery of analgesics with improved safety profiles. This work continues the work of the completed R21 (NIDA DA019620) entitled, "In Vivo Screening of Mixture-Based Combinatorial Libraries". The overall approach described herein will accelerate drug discovery and the subsequent identification of more advanced therapeutic candidates poised for preclinical studies. The traditional approach to small molecule drug discovery is to identify individual compounds through in vitro HTS assays, before selected compounds are tested in vivo. However, such a late transition to animal testing fosters a high rate of attrition that is costly in both time and research dollars. To circumvent this problem, this proposal utilizes a novel translational approach capable of eliminating non-efficacious compounds at the earliest stage. The long-term goal of these studies is to apply in vivo HTS to accelerate drug discovery in multiple therapeutic areas. As the first step towards that goal, the specific objective in the present application applies this technique to address the need for potent, but inherently safer, analgesic compounds. Marketed opioid analgesics are both potent and effective, but are strongly addictive with potentially life- threatening side effects. This proposal will identify new chemical entities (NCEs) with the potential to advance to human clinical trials and, if successful, improve patients' quality of life while reducing the societal problems posed by nonmedical use of opioid analgesics. The potential of this proposal is clearly supportive of the mission of NIDA, "to lead the Nation in bringing the power of science to bear on drug abuse and addiction." The research design uses a method of screening large, mixture-based libraries in vivo to identify compounds that are active in an in vivo mouse model of nociception. A total of 37 available, in-house, small molecule library mixtures (representing over 7 million small molecules) will be screened in vivo with animal models of antinociception to identify additional scaffolds for development, complementing a previously identified scaffold. Individual compounds selected from these three scaffolds will be synthesized and purified for additional development which will include in vitro analysis, pharmaceutical profiling, and additional in vivo models. Ultimately, we will examine multiple scaffolds and select 2-3 new chemical entities to initiate preclinical studies. By the end of the proposed study, we will have clearly demonstrated the utility of combining large mixture- based libraries of small molecules with in vivo screening (in vivo HTS) to identify therapeutic hits and leads with demonstrated efficacy and minimized side effects. By utilizing in vivo HTS, compounds may be identified with in vivo efficacies that function through previously unidentified biological pathways, providing potential advances in both the clinical and scientific realms. PUBLIC HEALTH RELEVANCE: This proposal utilizes a new methodology which has the potential to accelerate drug discovery in multiple therapeutic areas. Highly innovative approaches now permit literally millions of compounds to be tested in animal models at a very early stage of the discovery process. Initial studies will be targeted toward the identification of small molecules useful for the treatment of pain and that lack the negative effects of existing pain medications (addiction potential, respiratory depression, tolerance and psychological effects).

描述（由申请人提供）：拟议的研究的中心工作假设是，直接体内高吞吐量筛选（体内HTS）将产生增强的铅，从而加速具有改善安全剖面的止痛药。这项工作延续了完整的R21（NIDA DA019620）的工作，标题为“基于混合物的组合库的体内筛选”。本文描述的总体方法将加速药物发现，并随后鉴定有助于临床前研究的更先进的治疗候选者。传统的小分子药物发现方法是在体内测试选定的化合物之前，通过体外HTS分析鉴定单个化合物。但是，这样的晚期过渡到动物测试促进了高损耗率，这在时间和研究美元上都是昂贵的。为了解决这个问题，该提案采用了一种新型的翻译方法，能够在最早的阶段消除非效率化合物。这些研究的长期目标是将体内HTS应用于多个治疗区域的药物发现。作为朝着该目标的第一步，本应用程序中的特定目标应用了该技术来满足对有效但固有更安全的镇痛化合物的需求。市场上销售的阿片类镇痛药既有效又有效，但具有强烈的上瘾，可能会威胁生命的副作用。该建议将确定新的化学实体（NCE），有可能进步进行人类临床试验，并在成功的同时改善患者的生活质量，同时减少非医学使用阿片类镇痛药所带来的社会问题。该提案的潜力显然支持NIDA的使命，“带领国家带来科学的力量来承受滥用药物和成瘾”。研究设计使用一种在体内筛选基于混合物的大型库的方法，以识别在体内小鼠伤害感受模型中活跃的化合物。总共有37种可用的内部，小分子库混合物（代表700万个小分子）将在体内筛选，并使用抗伤害感受吸引力的动物模型，以鉴定出开发的其他支架，并补充先前鉴定的脚手架。从这三个脚手架中选择的各个化合物将被合成并纯化，以进行其他开发，其中包括体外分析，药物分析和其他体内模型。最终，我们将检查多个脚手架，并选择2-3个新的化学实体来启动临床前研究。在拟议的研究结束时，我们将清楚地证明，将大型分子的大型混合物库与体内筛选（体内HTS）相结合，以鉴定具有功效和最小化副作用的治疗效果和铅。通过利用体内HTS，可以通过体内效率鉴定出通过先前未识别的生物学途径发挥作用的体内效率，从而在临床和科学领域都提供了潜在的进步。公共卫生相关性：该提案采用了一种新方法，该方法有可能在多个治疗领域加速药物发现。现在，高度创新的方法允许在发现过程的早期阶段，在动物模型中可以在动物模型中进行数百万种化合物。初步研究将针对鉴定用于治疗疼痛的小分子，并且缺乏现有止痛药的负面影响（成瘾潜力，呼吸抑郁症，耐受性和心理影响）。