Optimization of Antischistosomal Chemotypes

抗血吸虫化学型的优化

基本信息

批准号：
8998926
负责人：
Jonathan L Vennerstrom
金额：
$ 59.87万
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/8998926
关键词：
Action Potentials Adolescent Adult Adverse effects Affect Affinity Alkylation Androgen Receptor Antibodies Area Binding Proteins Biological Assay Blood Carboxylic Acids Chemicals Computer Simulation Country Data Databases Dose Drug Kinetics Drug Targeting Drug resistance Feedback Glean Goals Health Human Hydantoins Immunofluorescence Immunologic In Vitro Individual Infection Investigation Knowledge Lead Life Ligand Binding Link Metabolic Microsomes Mission Mus Oral Outcome Parasites Parasitic Diseases Permeability Pharmaceutical Preparations Plasma Proteins Praziquantel 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 novel therapeutics programs prospective 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（申请人提供）：血吸虫病是一种由血吸虫属吸虫感染引起的热带寄生虫病，影响全球多达 4.4 亿人，其中 7.79 亿人面临感染风险。迫切需要一种治疗血吸虫病的新药。由于吡喹酮是目前的最后手段，耐药性的发展不容忽视，特别是考虑到其在许多地方病中的大规模使用，我们的长期目标是发现一种新的口服活性单剂量抗血吸虫药物。该提案的目的是确定一种或多种抗血吸虫药物开发候选药物，以实现针对所有寄生虫阶段的活性，我们将优化四种有前景的抗血吸虫化学型。 - 臭氧化物、芳基乙内酰脲、脲羧酸和 N,N'-二芳基脲：1) 合成和表征目标化合物；2) 评估目标化合物的药代动力学和抗血吸虫活性；3) 进一步分析。使用更严格的分析方法选择目标化合物；4) 启动优化目标化合物的作用机制 (MOA) 研究，化合物设计将根据现有的 SAR 进行优化。由前瞻性计算机物理化学分析指导的结构多样性基于物理化学分析、体外 ADME 和细胞毒性 (SA 1)、离体和体内抗血吸虫活性以及体内 ADME（SA 2 和 3）的迭代反馈，新的结构假设。将会出现，并且我们将合成其他目标化合物。我们认为这项拟议的研究具有创新性，原因有几个。前三种化学型（臭氧化物、芳基乙内酰脲、脲羧酸）已被证明具有体内抗血吸虫功效，但体外（体内）活性非常低甚至没有，这与先导化合物的通常情况相反因此，对这些化学型的机制研究可能会产生新的血吸虫病治疗方法/药物靶标。其次，对于芳基乙内酰脲，我们概述了一种通过利用负 SAR 来减少抗雄激素副作用的设计策略。从雄激素受体 (AR) 配体结合研究中收集的数据，旨在降低而不是增加 AR 结合亲和力。这项工作的预期结果是鉴定一种或多种抗血吸虫药物。开发候选药物对所有寄生虫阶段均有效，并具有新颖的作用机制。这项拟议的研究意义重大，因为新药在耐药血吸虫病的化疗中非常重要，并且可能在遏制这种寄生虫病的综合控制计划中有价值。