Optimization of Antischistosomal Chemotypes

抗血吸虫化学型的优化

基本信息

批准号：
8861056
负责人：
Jonathan L Vennerstrom
金额：
$ 62.39万
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：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8861056
关键词：
Action Potentials Adolescent Adult Adverse effects Affect Affinity Alkylation Androgen Receptor Antibodies Area Biological Assay Blood Carboxylic Acids Chemicals Computer Simulation Country Data Databases Dose Drug Kinetics Drug Targeting Drug resistance Feedback Glean Goals Human Hydantoins Immunofluorescence Immunologic In Vitro Individual Infection Inhibitory Concentration 50 Investigation Knowledge Lead Life Ligand Binding Link Metabolic Microsomes Mission Mus Oral Outcome Parasites Parasitic Diseases Permeability Pharmaceutical Preparations Plasma Proteins Praziquantel Protein Binding Protein Isoforms Proteins Proteomics Public Health Rattus Research Resistance development Resort Risk Schistosoma Schistosoma japonicum Schistosoma mansoni Schistosomiasis Series Solubility Staging Structure-Activity Relationship Titrations Treatment Failure Trematoda Urea Work base chemotherapy cytotoxicity design drug development genotoxicity in vivo indexing innovation novel novel therapeutic intervention programs prospective public health relevance 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 as many as 440 million individuals worldwide, with 779 million living at risk of infection. 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. 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 is to identify one or more antischistosomal drug development candidates. To accomplish this objective, we will optimize four promising antischistosomal chemotypes - ozonides, aryl hydantoins, urea carboxylic acids, and N,N'-diarylureas. We propose four specific aims: 1) to synthesize and characterize target compounds; 2) to assess pharmacokinetics and antischistosomal activity of target compounds; 3) to further profile selected target compounds using more rigorous assays; and 4) to initiate mechanism of action (MOA) studies for optimized target compounds. Compound design will be informed by existing SAR and will maximize structural diversity guided by prospective in silico physicochemical profiling. Based on iterative feedback from physicochemical profiling, in vitro ADME, and cytotoxicity (SA 1), ex vivo and in vivo antischistosomal activity and in vivo ADME (SA 2 and 3), new structural hypotheses will arise, and we will synthesize additional target compounds. Target compounds will progress through the various assays using clearly defined progression criteria. We suggest that this proposed research is innovative for several reasons. First, the first three chemotypes (ozonides, aryl hydantoins, urea carboxylic acids) have proven in vivo antischistosomal efficacy, but have very low to no ex vitro (in vivo) activity, the reverse of the usual situation where lead compounds have in vitro but no in vivo activity. Thus, mechanistic investigation of these chemotypes may lead to new therapeutic approaches/drug targets for schistosomiasis. Second, for the aryl hydantoins, we outline a design strategy to decrease antiandrogenic side effects by capitalizing on negative SAR data gleaned from androgen receptor (AR) ligand binding studies to decrease, not increase, AR binding affinity. The expected outcome from this work is to identify one or more antischistosomal drug development candidates effective against all parasite stages and with a novel mechanism of action. This proposed research is significant because a new drug would be important in the chemotherapy of drug-resistant schistosomiasis and likely be valuable in integrated control programs to curb this parasitic disease.

描述（由适用提供）：血吸虫病是一种由fluke菌的感染引起的热带寄生虫病，影响了全球多达4.4亿个人，有7.79亿人患有感染风险。急切的新药物是急切的由于普拉齐特尔目前是最后一个度假胜地的药物，因此不容忽视抗药性的药物，尤其是鉴于其在许多内部人体中的大规模使用。我们的长期目标是发现一种新的口服单剂量反毒素药物，其活性针对所有寄生虫阶段以及具有新颖的作用机理。该提案的目的是确定一个或多个反chistosomal药物开发候选者。为了实现这一目标，我们将优化四种有希望的反毒体化学型 - 臭氧，芳基水合物，尿素羧酸和N，N' -Diarelureas。我们提出了四个具体目标：1）合成和表征靶化合物； 2）评估靶化合物的药代动力学和抗心体活性； 3）使用更严格的评估进一步介绍选定的目标化合物； 4）启动作用机理（MOA）研究以进行优化的目标化合物。现有SAR将告知复合设计，并将最大程度地提高以硅物理分析的前瞻性指导的结构多样性。基于物理分析，体外ADME和细胞毒性的迭代反馈（SA 1），Ex Vivo和体内反静脉体活性以及体内ADME（SA 2和3），新的结构假设将出现，我们将合成其他靶标化合物。目标化合物将使用明确定义的进程标准进行各种测定法。我们建议这项拟议的研究具有创新性，原因有几个。首先，前三种化学型（臭氧，芳基水合物，尿素羧酸）已被证明在体内抗质体效率，但具有很低到没有过的体外（体内）活性，是常见情况的反向具有体外但没有体内活性。这是对这些化学型的机械研究可能导致血吸虫病的新治疗方法/药物靶标。其次，对于芳基水解蛋白，我们概述了一种设计策略，可以通过利用从雄激素受体（AR）配体结合研究收集的阴性SAR数据来减少抗雄激素副作用，以减少而不是增加AR结合亲和力。这项工作的预期结果是确定有效的一个或多个反chistosomal药物开发的候选候选者，并具有新颖的作用机理。这项拟议的研究很重要，因为一种新药在耐药的血吸虫病的化学疗法中很重要，并且可能在遏制这种寄生疾病的综合控制计划中很有价值。