Increasing the Antischistosomal Selectivity of Aryl Hydantoins

提高芳基乙内酰脲的抗血吸虫选择性

基本信息

批准号：
8523778
负责人：
Jonathan L Vennerstrom
金额：
$ 14.94万
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：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523778
关键词：
Acetates Adolescent Adult Adverse effects Affect Affinity Androgen Receptor Animal Model Area Bicalutamide Biological Assay Cell Line Cells Chemicals Country Cyproterone Acetate Data Databases Dose Drug resistance Feedback Fluorescence Polarization Flutamide Genetic Transcription Glean Goals Hydantoins Individual Infection Inhibitory Concentration 50 Knowledge Laboratories Lead Libraries Life Ligand Binding Ligands Link Mammalian Cell Mission Mus Nilutamide Oral Outcome Parasites Parasitic Diseases Pharmaceutical Preparations Pica Disease Praziquantel Property Public Health Reporter Research Resistance development Resort Risk Schistosoma Schistosoma mansoni Schistosomiasis Specificity Staging Testing Treatment Failure Trematoda Work analog base chemotherapy cytotoxicity design functional group in vivo innovation novel programs prototype receptor receptor binding research study

项目摘要

DESCRIPTION (provided by applicant): Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, affecting 200 million individuals worldwide. A new drug for schistosomiasis is urgently needed as praziquantel is currently the drug of last resort and the development of resistance cannot be ignored, particularly in view of its large-scale use in many endemic countries. Our long-term goal is to discover a new orally active single- dose antischistosomal drug with activities against all parasite stages and with a novel mechanism of action. The objective of this proposal, the first step in pursuit of this goal, is to se the orally active aryl hydantoin prototype Ro 13-3978, a close structural analogue of the androgen receptor (AR) antagonist nilutamide, as a starting point to identify one or more lead compounds with high antischistosomal efficacy and with minimal to no interaction with the host AR. Our central hypothesis is that for aryl hydantoins and related heterocycles, the structural requirements for antischistosomal efficacy and AR binding interactions are divergent. This hypothesis arose on the basis of preliminary data produced in the applicant's laboratories. The rationale that underlies this research is to separate the desirable multi-stage antischistosomal properties of aryl hydantoins and related heterocycles from the undesirable antiandrogenic side effects in the host. Our central hypothesis will be tested by pursuing three specific aims: 1) To synthesize and characterize a structurally diverse library of Ro 13-3978 analogs; 2) To assess schistosomicidal activities of target compounds against S. mansoni; and 3) To determine target compound AR binding affinity [and cytotoxicity.] Our target compound design maximizes structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-AR interactions. This approach is innovative because our strategy to decrease side effects caused by host AR antagonism capitalizes on negative SAR data gleaned from AR ligand binding studies to decrease, not increase, AR binding affinity. The expected outcomes from this work are as follows. First, we will gain a new understanding of the structural specificit of AR binding vs. antischistosomal efficacy for aryl hydantoins and related heterocycles. Second, one or more structurally novel orally-active lead compounds with high antischistosomal selectivity will likely be identified. This proposed research is significant because it will provid the required data to justify the more labor-intensive multi-dimensional lead optimization effort to discover a new and inexpensive orally active single-dose antischistosomal drug with activities against all parasite stages and with a novel mechanism of action. Such a drug would be important in the chemotherapy of drug-resistant schistosomiasis and likely be valuable in integrated control programs to curb schistosomiasis.

描述（由申请人提供）：血吸虫病是一种热带寄生疾病，是由fluke属的感染引起的，该疾病在全球范围内影响了2亿个个体。迫切需要一种针对血吸虫病的新药物，因为普拉齐特尔目前是最后一种度假胜地的药物，并且不容忽视抵抗的发展，尤其是鉴于其在许多地方性国家中的大规模使用。我们的长期目标是发现一种新的口服单剂量抗合物体药物，其活性针对所有寄生虫阶段，并具有新颖的作用机理。 The objective of this proposal, the first step in pursuit of this goal, is to se the orally active aryl hydantoin prototype Ro 13-3978, a close structural analogue of the androgen receptor (AR) antagonist nilutamide, as a starting point to identify one or more lead compounds with high antischistosomal efficacy and with minimal to no interaction with the host AR.我们的中心假设是，对于芳基羟托蛋白和相关的杂环，抗毒体功效和AR结合相互作用的结构要求是不同的。该假设是基于申请人实验室产生的初步数据。这项研究基础的基本原理是将芳基氢素蛋白和相关杂环的理想多阶段反静脉体特性与宿主中不良的抗高血压副作用分开。我们的中心假设将通过追求三个具体目标来检验：1）合成和表征RO 13-3978类似物的结构多样性的库； 2）评估靶化合物针对曼氏链球菌的靶标活性； 3）为确定靶标的AR结合亲和力[和细胞毒性。]我们的靶化合物设计通过掺入可减少配体AR相互作用已知的子结构和官能团来指导结构多样性。这种方法具有创新性，因为我们降低宿主AR拮抗作用的副作用的策略利用了来自AR配体结合研究收集的负SAR数据，以减少而不是增加，AR结合亲和力。这项工作的预期结果如下。首先，我们将对AR结合的结构特异性与抗疾病体疗效的结构特异性有了新的了解。其次，可能会发现一种或多种结构新颖的口腔活性铅化合物，具有高抗毒体选择性。这项拟议的研究很重要，因为它将提供所需的数据，以证明更加劳动密集型的多维铅优化工作是合理的发现一种新的且廉价的口服单剂量抗合体药物，具有针对所有寄生虫阶段的活性以及具有新颖的作用机理。这样的药物在耐药血吸虫病的化学疗法中很重要，并且在遏制血吸虫病的综合控制计划中可能很有价值。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antischistosomal versus antiandrogenic properties of aryl hydantoin Ro 13-3978.

芳基乙内酰脲 Ro 13-3978 的抗血吸虫特性与抗雄激素特性。

DOI：
10.4269/ajtmh.14-0029
发表时间：
2014
期刊：
The American journal of tropical medicine and hygiene
影响因子：
0
作者：
Wang,Chunkai;Zhao,Qingjie;Min,Jaeki;Muniyan,Sakthivel;Vargas,Mireille;Wang,Xiaofang;Dong,Yuxiang;Guy,RKiplin;Lin,Ming-Fong;Keiser,Jennifer;Vennerstrom,JonathanL
通讯作者：
Vennerstrom,JonathanL

Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry.

液相色谱-串联质谱法测定未感染小鼠中抗血吸虫臭氧化铅 OZ418 的药代动力学。