Trematocidal Synthetic Perioxides

杀吸虫合成过氧化物

基本信息

批准号：
7648067
负责人：
Jonathan L Vennerstrom
金额：
$ 15.81万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2010-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7648067
关键词：
Acids Acute Adamantane Address Adolescent Adult Affect Bile fluid Biological Assay Carboxylic Acids Cells Characteristics Chemicals Chronic Clonorchis sinensis Country Cyclohexanes Data Disease Dose Drug Combinations Drug Kinetics Drug resistance Ensure Enzymes Fasciola hepatica Fascioliasis Feedback Goals Hepatic Hepatica Human In Vitro Infection Inhibitory Concentration 50 Investigation Lead Libraries Liver diseases Measures Metabolic Metabolism Modeling Molecular Target Morbidity - disease rate Muscle Myoblasts Oral Parasites Peroxides Pharmaceutical Preparations Plant Roots Plasmodium falciparum Praziquantel Prevention Prodrugs Property Protein Isoforms Rattus Resistance development Rural Screening procedure Skeletal Muscle Staging Surface Testing Toxic effect Treatment Efficacy Vaccines analog base cytotoxicity design disorder prevention drug development flexibility foodborne functional group in vitro testing in vivo insight novel process optimization public health relevance research study triclabendazole

项目摘要

DESCRIPTION (provided by applicant): Food-borne trematodiases affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of food-borne tremotodiases, effective drugs are the only practical means of morbidity control. Importantly, new drugs for these diseases are urgently needed as praziquantel and triclabendazole are the only drugs available and the development of resistance cannot be ignored, particularly in view of the large- scale use of praziquantel in many endemic countries. At the root of this project is our discovery that several synthetic peroxides also possess strong trematocidal activity. We propose to further explore the potential of synthetic peroxides as novel trematocidal drugs. The identification of a new, broad-spectrum, orally-active synthetic peroxide trematocidal drug development candidate will minimize drug-resistance and lead to superior treatment and control options for food-borne trematodiases. Essential characteristics of a new drug development candidate include an economically-feasible and scalable synthesis, excellent oral activity, low potential for toxicity and resistance development, broad spectrum of trematocidal activity, and high efficacy against all parasite stages in the vertebrate host. More specifically, our objective is to identify a drug development candidate with 100% worm burden reductions against juvenile and adult F. hepatica and C. sinensis at doses of < 100 mg/kg and with an excellent ADME profile (predicted ER < 0.30, CYP450 IC50s > 25 5M, oral BA > 30%). To address this overarching objective, we propose the following three specific aims: Specific Aim 1: To synthesize and characterize a focused and structurally diverse library of synthetic peroxides. Specific Aim 2: To assess trematocidal activity and selectivity of target synthetic peroxides against two major human food-borne trematode species, Fasciola hepatica and Clonorchis sinensis. Specific Aim 3: To determine metabolism and pharmacokinetic parameters and initiate mechanism of action studies for selected synthetic peroxides. PUBLIC HEALTH RELEVANCE Food-borne trematodiases, caused by infection with liver flukes, affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of these diseases, new drugs are urgently needed. Praziquantel and triclabendazole are the only drugs now available and the development of resistance cannot be ignored, particularly in view of the large-scale use of praziquantel in many endemic countries. In this proposal, we propose to identify a new broad-spectrum orally-active trematocidal drug development candidate.

描述（由申请人提供）：食源性吸虫病影响数亿人，特别是发展中国家的农村贫困人口。由于目前尚无疫苗，并且不太可能很快出现用于预防食源性震颤病的疫苗，因此有效的药物是控制发病率的唯一实用手段。重要的是，迫切需要治疗这些疾病的新药，因为吡喹酮和三氯苯达唑是唯一可用的药物，而且耐药性的发展不容忽视，特别是考虑到许多流行国家大规模使用吡喹酮。该项目的根源是我们发现几种合成过氧化物也具有很强的杀吸虫活性。我们建议进一步探索合成过氧化物作为新型杀吸虫药物的潜力。确定一种新的、广谱的、口服活性的合成过氧化物杀吸虫候选药物开发候选药物将最大限度地减少耐药性，并为食源性吸虫病提供更好的治疗和控制选择。新药开发候选药物的基本特征包括经济可行且可扩展的合成、优异的口服活性、低毒性和耐药性发展潜力、广谱杀吸虫活性以及对脊椎动物宿主中所有寄生虫阶段的高效。更具体地说，我们的目标是确定一种药物开发候选药物，在剂量 < 100 mg/kg 的情况下，对幼年和成虫肝片线虫和中华线虫的蠕虫负担降低 100%，并且具有出色的 ADME 特征（预测 ER < 0.30，CYP450） IC50 > 25 5M，口服 BA > 30%）。为了实现这一总体目标，我们提出以下三个具体目标：具体目标 1：合成并表征一个重点突出、结构多样的合成过氧化物库。具体目标 2：评估目标合成过氧化物对两种主要人类食源性吸虫（肝片形吸虫和华支睾吸虫）的杀吸虫活性和选择性。具体目标 3：确定代谢和药代动力学参数，并启动选定合成过氧化物的作用机制研究。公共卫生相关性由肝吸虫感染引起的食源性吸虫病影响着数亿人，特别是发展中国家的农村贫困人口。由于目前还没有疫苗，而且不太可能很快就可以用于预防这些疾病，因此迫切需要新药。吡喹酮和三氯苯达唑是目前唯一可用的药物，耐药性的发展不容忽视，特别是考虑到许多流行国家大规模使用吡喹酮。在本提案中，我们建议确定一种新的广谱口服活性杀吸虫药物开发候选药物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.

臭氧化物羧酸 (OZ78) 对抗肝片形吸虫的构效关系。

DOI：
10.1021/jm100226t
发表时间：
2010-05-27
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Zhao Q;Vargas M;Dong Y;Zhou L;Wang X;Sriraghavan K;Keiser J;Vennerstrom JL
通讯作者：
Vennerstrom JL

Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni.

OZ78 类似物对抗肝片形吸虫和卡普罗尼棘口吸虫的活性。

DOI：
10.1016/j.actatropica.2011.02.003
发表时间：
2011-04
期刊：
Acta tropica
影响因子：
2.7
作者：
Kirchhofer, Carla;Vargas, Mireille;Braissant, Olivier;Dong, Yuxiang;Wang, Xiaofang;Vennerstrom, Jonathan L.;Keiser, Jennifer
通讯作者：
Keiser, Jennifer

Activity of antiandrogens against juvenile and adult Schistosoma mansoni in mice.

抗雄激素对小鼠幼年和成年曼氏血吸虫的活性。

DOI：
发表时间：
2010-09
期刊：
影响因子：
0
作者：
Keiser, Jennifer;Vargas, Mireille;Vennerstrom, Jonathan L
通讯作者：
Vennerstrom, Jonathan L

The activity of dispiro peroxides against Fasciola hepatica.

二螺过氧化物对肝片形吸虫的活性。

DOI：
发表时间：
2011-09-15
期刊：
影响因子：
2.7
作者：
Wang, Xiaofang;Zhao, Qingjie;Vargas, Mireille;Dong, Yuxiang;Sriraghavan, Kamaraj;Keiser, Jennifer;Vennerstrom, Jonathan L
通讯作者：
Vennerstrom, Jonathan L

In vivo activity of aryl ozonides against Schistosoma species.

芳基臭氧化物对血吸虫的体内活性。

DOI：
发表时间：
2012-02
期刊：
影响因子：
4.9
作者：
Keiser, Jennifer;Ingram, Katrin;Vargas, Mireille;Chollet, Jacques;Wang, Xiaofang;Dong, Yuxiang;Vennerstrom, Jonathan L
通讯作者：
Vennerstrom, Jonathan L