Optimization of Antischistosomal Chemotypes

抗血吸虫化学型的优化

• 批准号: 10598486
• 负责人: Jonathan L Vennerstrom
• 金额: $ 61.96万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598486
• 关键词: Adolescent; Adult; Affect; Area; Binding Proteins; Biological Assay; Blood; Country; Databases; Dose; Drug Kinetics; Drug resistance; Feedback; Goals; Human; Hydantoins; In Vitro; Individual; Indoles; Infection; Investigation; Knowledge; Lactams; Lead; Mediating; Metabolic; Microsomes; Mission; Mus; Oral; Outcome; Parasites; Parasitic Diseases; Pathway Analysis; Periodicity; Permeability; Pharmaceutical Preparations; Plasma Proteins; Praziquantel; Property; Protein Isoforms; Proteins; Public Health; Rattus; Research; Resistance development; Ring Compound; Role; Schistosoma; Schistosoma japonicum; Schistosoma mansoni; Schistosomiasis; Series; Solubility; Structure-Activity Relationship; Sulfonamides; Titrations; Treatment Failure; Trematoda; United States National Institutes of Health; Work; adaptive immune response; chemotherapy; cytotoxicity; design; drug action; drug candidate; drug development; experimental study; genotoxicity; in silico; in vivo; indexing; infection risk; innovation; novel; novel therapeutics; programs; prospective; transcriptomics

Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, affecting as many as 200 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. We will also continue our investigation into the host-­mediated antischistosomal mode of action of aryl hydantoin drug candidate AR102. We propose four specific aims: 1) to synthesize and characterize target compounds; 2) to assess pharmacokinetic properties and antischistosomal activity of target compounds; 3) to further profile selected target compounds using more rigorous assays; and 4) to investigate the mode of action of drug candidate AR102. 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 aryl hydantoins and ozonides have proven in vivo antischistosomal efficacy, but have very low ex vivo (in vitro) activity, the reverse of the usual situation where lead compounds have in vitro but no in vivo activity. Second, the azonine keto lactam chemotype and backup tricyclic imidazolidin-­4-­one compound series are examples of relatively rare medium-­ring compounds (8 to 11 atoms). Third, we seek to demarcate the unique host-­mediated mode of action of antischistosomal drug candidate AR102. The expected outcome from this work is to identify one or more antischistosomal drug development candidates effective against all parasite stages. For antischistosomal drug candidate AR102, we will define its host-­mediated antischistosomal mode 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.

血吸虫病是一种热带寄生虫病，由血吸虫属吸虫感染引起， 影响到全世界多达2亿人，其中7.79亿人面临感染风险。的新药 由于吡喹酮是目前最后的药物， 耐药性不容忽视，特别是考虑到它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寄生虫药物， with a novel新mechanism机制of action行动.本提案的目的是鉴定一种或多种抗组胺药， 药物开发候选人。为了实现这一目标，我们将优化四个有前途的抗肿瘤药物， 化学型我们还将继续研究宿主介导的抗血吸虫作用方式 芳基乙内酰脲候选药物AR 102。我们提出了四个具体目标：1）合成和表征目标化合物， 化合物; 2）评估靶化合物的药代动力学性质和抗溶酶体活性; 3） 使用更严格的测定进一步分析选定的目标化合物;和4）研究作用模式 候选药物AR 102。化合物设计将根据现有SAR进行， 多样性由前瞻性计算机物理化学分析指导。根据来自以下机构的反复反馈， 理化分析、体外ADME和细胞毒性（SA 1）、离体和体内抗溶酶体活性 和体内ADME（SA 2和3），新的结构假设将出现，我们将合成额外的目标， 化合物.目标化合物将通过使用明确定义的进展的各种测定来进展 的搜索.我们认为，这项拟议的研究是创新的，原因有几个：首先，芳基乙内酰脲和 臭氧化物已被证明具有体内抗溶酶体功效，但离体（体外）活性非常低，相反， 通常情况下，先导化合物在体外具有活性，但在体内没有活性。第二，氮杂酮 内酰胺化学型和后备三环咪唑烷-β 4-吡喃酮化合物系列是相对罕见 中碳环化合物（8至11个原子）。第三，我们试图界定独特的宿主介导模式， 抗肿瘤药物候选物AR 102的作用。这项工作的预期成果是确定一个或 更多的抗寄生虫体药物开发候选物对所有寄生虫阶段有效。抗组胺药 对于候选药物AR 102，我们将确定其宿主介导的抗溶酶体作用模式。这一拟议 研究是有意义的，因为一种新的药物在耐药的化疗中是重要的。 血吸虫病和可能是有价值的综合控制计划，以遏制这种寄生虫病。