Lead Optimization of Bis-benzimidazole Analogs for Pathogenic Free-living Amoebae
双苯并咪唑类似物针对致病性自由生活阿米巴原虫的先导化合物优化
基本信息
- 批准号:9090018
- 负责人:
- 金额:$ 9.61万
- 依托单位:
- 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:2015-06-15 至 2016-12-29
- 项目状态:已结题
- 来源:
- 关键词:AcanthamoebaAmoeba genusAmphotericin BAnimalsBacteriaBiological AssayBlood - brain barrier anatomyBrainCell SurvivalCentral Nervous System InfectionsCessation of lifeChronic DiseaseClinicalCombined Modality TherapyCystDataDevelopmentDiagnosisDiseaseDisease modelDoseEmerging Communicable DiseasesEnvironmentFatality rateFresh WaterGoalsGranulomatousHealthHumanImmunocompromised HostIn VitroInfectionKeratitisLeadLibrariesLifeLiteratureMarinesMastigophoraMedicalMiltefosineModelingMusNaegleriaNaegleria fowleriNatureNeuraxisNeurologicOpportunistic InfectionsPenetrationPermeabilityPharmaceutical PreparationsPharmacologic SubstancePharmacotherapyPhasePropertyRegimenResearchRiskSafetySalineSeriesSeveritiesSkinSoilStructureTherapeuticToxic effectToxicologyValidationanalogantimicrobial drugbasebenzimidazole analogbis-benzimidazoledrug developmentdrug discoveryfeedingimprovedin vitro Assayin vivokillingsneglectnervous system disordernovelnovel therapeuticspathogenpreventprimary amebic meningoencephalitisresponsescaffoldscreening
项目摘要
DESCRIPTION (provided by applicant): Small, free-living amoebae (FLA) are ubiquitous in nature and are found in soil, fresh water, and marine environments. Most of the FLA feed on bacteria and are of no medical importance, yet several genera and species of FLA are known to causes serious, usually fatal disease in humans and animals. Naegleria fowleri and Acanthamoeba spp. are the best known examples of pathogenic FLA. N. fowleri thrives in warm, freshwater and is the causative agent of primary amoebic meningoencephalitis (PAM). This disease is characterized by a fulminant, rapidly fatal encephalitic disease that most often afflicts healthy young humans. Acanthamoeba spp. are more ubiquitous and found in water (fresh and saline) and soil. Multiple species of Acanthamoeba are known to cause granulomatous amoebic encepahalitis (GAE), a chronic disease seen most often in immunocompromised hosts and those at risk of opportunistic infections. Acanthamoeba spp. also causes amoebic keratitis, skin, nasopharyngeal, and disseminated infections. The major problem for infections with any of the pathogenic FLA is the lack of effective therapeutics. PAM and GAE are usually fatal diseases, even if the infection is diagnosed promptly and treated with the best available drug regimens. Despite the severity of infections caused by FLA, there are few data available on new drugs and no concerted modern drug discovery or development efforts. The majority of the research literature on drug discovery for FLA consists of limited in vitro or in vivo studies with drugs already approved for other uses. The major goals of this project are to discover and develop and to late lead ≥ one new drug to treat central nervous system infections with pathogenic FLA. We have conducted structure activity studies with a series of amidino related compounds (>160) and identified two chemotypes for further development. In the R21 phase, we propose to conduct additional lead optimization to develop early lead candidates by the end of the R21 phase. Candidates will be prioritized based upon in vitro potency, physiochemical properties, and rate-of-killing in a novel dual cell viability assay.In the R33 phase we will further optimize for potency in vivo and enhancement of PK and ADME properties and conduct safety toxicology studies with the best late lead candidates. Our ultimate goal for this project is to identify one novel amidino related compound that can be used in combination with other drugs for the treatment of pathogenic FLA infections of the central nervous system.
描述(由申请人提供):小型、自由生活的阿米巴原虫(弗拉)在自然界中普遍存在,存在于土壤、淡水和海洋环境中。大多数弗拉以细菌为食,并且没有医学重要性,但已知弗拉的几个属和种在人类和动物中引起严重的,通常是致命的疾病。福氏耐格里原虫和阿米巴原虫。是致病性弗拉最著名的例子。N. Fowleri在温暖的淡水中生长,是原发性阿米巴脑膜脑炎(PAM)的病原体。这种疾病的特点是一种暴发性、迅速致命的脑炎,最常折磨健康的年轻人。阿米巴属更常见于水(淡水和盐水)和土壤中。已知多种阿米巴属可引起肉芽肿性阿米巴脑炎(GAE),这是一种最常见于免疫功能低下宿主和有机会性感染风险的宿主的慢性疾病。阿米巴属还引起阿米巴角膜炎、皮肤炎、鼻咽炎和播散性感染。任何致病性弗拉感染的主要问题是缺乏有效的治疗方法。PAM和GAE通常是致命的疾病,即使感染被及时诊断并用最好的药物方案治疗。尽管弗拉引起的感染很严重,但关于新药的数据很少,也没有协调一致的现代药物发现或开发工作。大多数关于弗拉药物发现的研究文献包括已批准用于其他用途的药物的有限体外或体内研究。本项目的主要目标是发现、开发和后期领导至少一种治疗致病性弗拉中枢神经系统感染的新药。我们已经对一系列脒基相关化合物(>160)进行了结构活性研究,并确定了两种化学型供进一步开发。在R21阶段,我们建议进行额外的潜在客户优化,以便在R21阶段结束时开发早期潜在客户候选人。在R33阶段,我们将进一步优化候选药物的体内效价,增强PK和ADME特性,并对最佳的晚期先导候选药物进行安全性毒理学研究。本项目的最终目标是确定一种新的脒基相关化合物,可与其他药物联合用于治疗中枢神经系统的致病性弗拉感染。
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)
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DENNIS E KYLE其他文献
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{{ truncateString('DENNIS E KYLE', 18)}}的其他基金
Elucidating mechanisms for artemisinin-induced dormancy in Plasmodium falciparum
阐明青蒿素诱导恶性疟原虫休眠的机制
- 批准号:
10742385 - 财政年份:2023
- 资助金额:
$ 9.61万 - 项目类别:
Lead optimization and target identification of drugs targeting hypnozoites
催眠药物的先导化合物优化和靶点识别
- 批准号:
10035076 - 财政年份:2020
- 资助金额:
$ 9.61万 - 项目类别:
Lead optimization and target identification of drugs targeting hypnozoites
催眠药物的先导化合物优化和靶点识别
- 批准号:
10455026 - 财政年份:2020
- 资助金额:
$ 9.61万 - 项目类别:
Lead optimization and target identification of drugs targeting hypnozoites
催眠药物的先导化合物优化和靶点识别
- 批准号:
10688200 - 财政年份:2020
- 资助金额:
$ 9.61万 - 项目类别:
Lead optimization and target identification of drugs targeting hypnozoites
催眠药物的先导化合物优化和靶点识别
- 批准号:
10231087 - 财政年份:2020
- 资助金额:
$ 9.61万 - 项目类别:
Combining Liver Stage Culture System with Backcross Genetics to Discover Antimalarial Drug Resistance Loci
肝阶段培养系统与回交遗传学相结合发现抗疟药物耐药位点
- 批准号:
9891003 - 财政年份:2019
- 资助金额:
$ 9.61万 - 项目类别:
Orally Bioavailable 4(1H)-Quinolones with Multi-Stage Antimalarial Activity
具有多阶段抗疟活性的口服生物可利用 4(1H)-喹诺酮类药物
- 批准号:
10598072 - 财政年份:2019
- 资助金额:
$ 9.61万 - 项目类别:
Orally Bioavailable 4(1H)-Quinolones with Multi-Stage Antimalarial Activity
具有多阶段抗疟活性的口服生物可利用 4(1H)-喹诺酮类药物
- 批准号:
10373024 - 财政年份:2019
- 资助金额:
$ 9.61万 - 项目类别:
Orally Bioavailable 4(1H)-Quinolones with Multi-Stage Antimalarial Activity
具有多阶段抗疟活性的口服生物可利用 4(1H)-喹诺酮类药物
- 批准号:
9913468 - 财政年份:2019
- 资助金额:
$ 9.61万 - 项目类别:
Extreme Resistance to Mitochondrial Inhibitors in Plasmodium falciparum
恶性疟原虫对线粒体抑制剂的极度耐药性
- 批准号:
8624359 - 财政年份:2014
- 资助金额:
$ 9.61万 - 项目类别: