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

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、自由生活的变形虫(FLA)在自然界中无处不在,存在于土壤、淡水和海洋环境中,大多数 FLA 以细菌为食,没有医学意义,但有几个属。众所周知,福氏耐格里变形虫和棘阿米巴属会导致人类和动物严重的、通常致命的疾病。福氏阿米巴菌在温暖的淡水中繁殖,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致命的暴发性脑炎疾病,最常见于健康的年轻人,这种疾病在水中更为普遍。已知多种棘阿米巴会引起肉芽肿性阿米巴病。脑炎 (GAE) 是一种最常见于免疫功能低下的宿主和有机会性感染风险的人的慢性疾病,也会引起阿米巴角膜炎、皮肤、鼻咽和播散性感染。任何致病性 FLA 感染的主要问题是。尽管感染得到及时诊断并采用最佳药物治疗,但缺乏有效的治疗方法,PAM 和 GAE 通常是致命的疾病。由于 FLA 引起的感染的严重性,关于新药的数据很少,并且没有协调一致的现代药物发现或开发工作。大多数关于 FLA 药物发现的研究文献包括有限的体外或体内研究,这些研究涉及已批准的药物。该项目的主要目标是发现和开发并后期开发一种治疗致病性 FLA 中枢神经系统感染的新药。我们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以进一步在 R21 阶段,我们建议在 R21 阶段结束时进行额外的先导化合物优化,以开发早期的先导候选药物。在 R33 阶段,我们将进一步优化体内效力并增强 PK 和 ADME 特性,并使用最佳的晚期先导候选物进行安全毒理学研究。我们该项目的最终目标是鉴定一种新型脒基相关化合物。能与其他药物联合用于治疗中枢神经系统致病性FLA感染。

项目成果

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DENNIS E KYLE其他文献

DENNIS E KYLE的其他文献

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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:
    9913468
  • 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:
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:

相似海外基金

Discovery of New Anti-amoeba Therapeutics
新抗阿米巴疗法的发现
  • 批准号:
    9480203
  • 财政年份:
    2015
  • 资助金额:
    $ 9.61万
  • 项目类别:
Discovery of New Anti-amoeba Therapeutics
新抗阿米巴疗法的发现
  • 批准号:
    8960084
  • 财政年份:
    2015
  • 资助金额:
    $ 9.61万
  • 项目类别:
Discovery of New Anti-amoeba Therapeutics
新抗阿米巴疗法的发现
  • 批准号:
    9495660
  • 财政年份:
    2015
  • 资助金额:
    $ 9.61万
  • 项目类别:
Discovery of New Anti-amoeba Therapeutics
新抗阿米巴疗法的发现
  • 批准号:
    9094675
  • 财政年份:
    2015
  • 资助金额:
    $ 9.61万
  • 项目类别:
New Therapies for Pathogenic Free-Living Amoebae
致病性自由生活阿米巴原虫的新疗法
  • 批准号:
    8650790
  • 财政年份:
    2013
  • 资助金额:
    $ 9.61万
  • 项目类别:
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