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:
- 金额:$ 40.8万
- 依托单位:
- 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:
- 关键词:AcuteAddressAdverse effectsAgonistAnalgesicsAnimal ModelAnimal TestingAreaBiologicalBiological AssayBiological SciencesChemicalsClinicalClinical TrialsComplementConstipationCyclic AMPDataDevelopmentDoseDrug AddictionDrug abuseEvaluationExhibitsFosteringGastrointestinal TransitGenerationsGoalsHousingHumanIn VitroIndividualLeadLibrariesLifeMarketingMeasuresMethodologyMethodsMissionNarcotic AntagonistsNational Institute of Drug AbuseNational Institute of Mental HealthNociceptionOpioidOpioid AnalgesicsPainPathway interactionsPatientsPharmaceutical ChemistryPharmacologic SubstancePositioning AttributePreclinical Drug EvaluationPrincipal InvestigatorProcessPropertyPsychotropic DrugsQuality of lifeResearchResearch DesignRespirationRouteSafetyScanningScienceScreening procedureSolubilityStagingTailTechniquesTestingTherapeuticTimeUrsidae FamilyVentilatory DepressionWaterWithdrawalWorkaddictionbasecombinatorialdrug discoveryhigh throughput screeningimprovedin vitro Assayin vitro activityin vitro testingin vivoin vivo Modelinflammatory neuropathic paininnovationinterestmouse modelnonmedical usenovelpre-clinicalpreclinical studypreferencepsychologicreceptor internalizationrespiratoryresponsescaffoldsmall moleculesmall molecule librariestranslational 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):拟定研究的中心工作假设是,直接体内高通量筛选(体内HTS)将产生增强的先导化合物,从而加速发现具有改善安全性特征的镇痛药。这项工作继续了已完成的R21(NIDA DA 019620)的工作,标题为“基于混合物的组合文库的体内筛选”。本文所述的整体方法将加速药物发现和随后对准备用于临床前研究的更先进的治疗候选物的鉴定。小分子药物发现的传统方法是在体内测试选定的化合物之前,通过体外HTS测定来鉴定单个化合物。然而,如此晚的向动物试验的过渡促进了高损耗率,这在时间和研究资金上都是昂贵的。为了避免这个问题,该提案利用了一种能够在最早阶段消除无效化合物的新型翻译方法。这些研究的长期目标是应用体内HTS来加速多个治疗领域的药物发现。作为实现该目标的第一步,本申请的具体目的是应用该技术来解决对有效但本质上更安全的镇痛化合物的需求。市售的阿片类镇痛药既强效又有效,但有很强的成瘾性,有潜在的危及生命的副作用。该提案将确定有可能进入人体临床试验的新化学实体(NCE),如果成功,将改善患者的生活质量,同时减少阿片类镇痛药的非医疗使用带来的社会问题。这项建议的潜力显然是支持NIDA的使命,“领导国家利用科学的力量来对付药物滥用和成瘾。“研究设计使用了一种在体内筛选大型混合物库的方法,以鉴定在体内小鼠伤害感受模型中具有活性的化合物。总共37个可用的内部小分子文库混合物(代表超过700万个小分子)将在抗伤害感受的动物模型中进行体内筛选,以确定用于开发的额外支架,补充先前确定的支架。从这三种支架中选择的单个化合物将被合成和纯化用于额外的开发,其将包括体外分析、药物分析和额外的体内模型。最终,我们将检查多种支架并选择2-3种新的化学实体来启动临床前研究。在所提出的研究结束时,我们将清楚地证明了将小分子的基于大混合物的文库与体内筛选(体内HTS)相结合以鉴定具有已证明的功效和最小化的副作用的治疗性命中和先导物的效用。通过利用体内HTS,化合物可以被鉴定为具有通过先前未鉴定的生物途径起作用的体内功效,从而在临床和科学领域两者中提供潜在的进步。
公共卫生相关性:该提案采用了一种新的方法,有可能加速多个治疗领域的药物发现。高度创新的方法现在允许在发现过程的早期阶段在动物模型中测试数百万种化合物。最初的研究将针对识别可用于治疗疼痛的小分子,并且没有现有止痛药的负面影响(成瘾潜力,呼吸抑制,耐受性和心理影响)。
项目成果
期刊论文数量(0)
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Richard Allen Houghten其他文献
Richard Allen Houghten的其他文献
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{{ truncateString('Richard Allen Houghten', 18)}}的其他基金
Novel cyclic lipopeptides for treating gram negative bacterial infections
用于治疗革兰氏阴性细菌感染的新型环状脂肽
- 批准号:
8956030 - 财政年份:2015
- 资助金额:
$ 40.8万 - 项目类别:
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
- 批准号:
8473840 - 财政年份:2011
- 资助金额:
$ 40.8万 - 项目类别:
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
- 批准号:
8661147 - 财政年份:2011
- 资助金额:
$ 40.8万 - 项目类别:
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
- 批准号:
8303201 - 财政年份:2011
- 资助金额:
$ 40.8万 - 项目类别:
In Vivo Screening of Mixture-Based Combinatorial Libraries
基于混合物的组合文库的体内筛选
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In Vivo Screening of Mixture-Based Combinatorial Libraries
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- 资助金额:
$ 40.8万 - 项目类别:
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- 批准号:
7683843 - 财政年份:2007
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