Increasing the Antischistosomal Selectivity of Aryl Hydantoins

描述(申请人提供)：血吸虫病是一种热带寄生虫病，由血吸虫属吸虫感染引起，影响全球2亿人。迫切需要一种治疗血吸虫病的新药，因为吡喹酮目前是最后的药物，抗药性的发展不能被忽视，特别是考虑到它在许多流行国家的大规模使用。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，具有抗所有寄生虫阶段的活性和新的作用机制。这项建议的目的是为了实现这一目标的第一步，是以口服活性的芳基海因原型RO13-3978为起点，作为鉴定一个或多个具有高抗血吸虫效果且与宿主AR几乎没有相互作用的先导化合物的起点。Ro 13-3978是雄激素受体(AR)拮抗剂的紧密结构类似物。我们的中心假设是，对于芳基海因和相关的杂环，抗血吸虫效果和AR结合相互作用的结构要求是不同的。这一假设是基于申请人实验室提供的初步数据而产生的。这项研究的理论基础是将芳基海因和相关杂环的理想多阶段抗血吸虫特性与宿主中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验证：1)合成和表征结构多样化的RO13-3978类似物库；2)评估目标化合物对曼氏血吸虫的血吸虫杀灭活性；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引入亚结构和已知的减少配体-AR相互作用的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数据来降低而不是增加AR结合亲和力。这项工作的预期成果如下。首先，我们将对芳基海因和相关杂环的AR结合与抗血吸虫疗效的结构特异性有一个新的理解。其次，可能会发现一种或多种结构新颖的口服活性先导化合物，具有较高的抗血吸虫选择性。这项拟议的研究具有重要意义，因为它将提供所需的数据，以证明更劳动密集型的多维线索优化工作是合理的 发现一种新的廉价的口服活性单剂量抗血吸虫药物，具有抗所有寄生虫阶段的活性和新的作用机制。这种药物将在耐药血吸虫病的化疗中发挥重要作用，并可能在遏制血吸虫病的综合控制计划中具有价值。 公共卫生相关性：这项拟议的研究与NIH的任务相关，因为它将产生关于雄激素受体结合与抗血吸虫疗效之间的结构特异性的新知识，并提供必要的数据，以证明发现新的抗血吸虫药物所需的更劳动密集型的多维先导优化工作是合理的。该项目与公共卫生相关，因为这种药物的发现将对抗药性血吸虫病的化疗具有重要意义，并可能对遏制这种寄生虫病的综合控制计划具有价值。

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.