Increasing the Antischistosomal Selectivity of Aryl Hydantoins

提高芳基乙内酰脲的抗血吸虫选择性

• 批准号: 8374010
• 负责人: Jonathan L Vennerstrom
• 金额: $ 20.82万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374010
• 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

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. PUBLIC HEALTH RELEVANCE: This proposed research is relevant to NIH's mission because it will generate new knowledge about the structural specificity of androgen receptor binding vs. antischistosomal efficacy and provide the required data to justify a more labor-intensive multi-dimensional lead optimization effort required to discover a new antischistosomal drug. The project is relevant to public health because the discovery of such a 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，影响全世界 2 亿人。由于吡喹酮是目前的最后手段，并且耐药性的发展不容忽视，特别是考虑到其在许多流行国家的大规模使用，因此迫切需要一种治疗血吸虫病的新药。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，该药物具有对抗所有寄生虫阶段的活性并具有新颖的作用机制。本提案的目的是实现这一目标的第一步，是寻找口服活性芳基乙内酰脲原型 Ro 13-3978，它是雄激素受体 (AR) 拮抗剂尼鲁米特的结构类似物，作为鉴定一种或多种具有高抗血吸虫功效且与宿主 AR 相互作用最小或没有相互作用的先导化合物的起点。我们的中心假设是，对于芳基乙内酰脲和相关杂环化合物，抗血吸虫功效和 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而产生的。这项研究的基本原理是将芳基乙内酰脲和相关杂环化合物所需的多阶段抗血吸虫特性与宿主体内不良的抗雄激素副作用分开。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 类似物的结构多样的文库； 2) 评估目标化合物对曼氏血吸虫的杀血吸虫活性； 3) 确定目标化合物 AR 结合亲和力 [和细胞毒性]。我们的目标化合物设计通过掺入已知可减少配体-AR 相互作用的子结构和官能团来最大化结构多样性。这种方法是创新的，因为我们减少宿主 AR 拮抗作用引起的副作用的策略利用了从 AR 配体结合研究中收集的负 SAR 数据来减少而不是增加 AR 结合亲和力。这项工作的预期成果如下。首先，我们将对芳基乙内酰脲和相关杂环化合物的 AR 结合与抗血吸虫功效的结构特异性有新的了解。其次，可能会鉴定出一种或多种具有高抗血吸虫选择性的结构新颖的口服活性先导化合物。这项拟议的研究意义重大，因为它将提供所需的数据来证明更加劳动密集型的多维先导优化工作的合理性 发现一种新型且廉价的口服活性单剂量抗血吸虫药物，具有对抗所有寄生虫阶段的活性和新颖的作用机制。这种药物在耐药血吸虫病的化疗中很重要，并且可能在遏制血吸虫病的综合控制计划中有价值。 公共健康相关性：这项拟议的研究与 NIH 的使命相关，因为它将产生关于雄激素受体结合的结构特异性与抗血吸虫功效的新知识，并提供所需的数据来证明发现新的抗血吸虫药物所需的更加劳动密集型的多维先导优化工作的合理性。该项目与公共卫生相关，因为这种药物的发现对于耐药血吸虫病的化疗非常重要，并且可能对于遏制这种寄生虫病的综合控制计划很有价值。