Increasing the Antischistosomal Selectivity of Aryl Hydantoins

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，影响全球2亿人。目前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，而且耐药性的发展不容忽视，特别是考虑到吡喹酮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单剂量抗血吸虫药，具有抗所有寄生虫阶段的活性，并具有新的作用机制。本研究的第一步是寻找具有口服活性的芳基酰肼原型Ro 13-3978，这是雄激素受体（AR）拮抗剂尼鲁胺的结构类似物，作为鉴定一种或多种具有高抗血吸虫功效且与宿主AR相互作用最小或不相互作用的先导化合物的出发点。我们的中心假设是，对于芳基酰肼和相关杂环，抗血吸虫功效和AR结合相互作用的结构要求是不同的。这一假设是根据申请人实验室产生的初步数据提出的。这项研究的基本原理是将芳基酰脲和相关杂环化合物在宿主体内的多阶段抗血吸虫特性与不希望的抗雄激素副作用分离开来。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的Ro 13-3978类似物库；2)评价目标化合物对曼氏梭菌的杀虫活性；3)测定靶化合物AR结合亲和力[和细胞毒性]。我们的目标化合物设计通过结合已知的减少配体- ar相互作用的亚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面SAR数据来降低而不是增加AR结合亲和力。本工作的预期成果如下：首先，我们将获得AR结合的结构特异性与芳基酰脲和相关杂环抗血吸虫功效的新认识。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，具有高抗血吸虫选择性。这一建议的研究是重要的，因为它将提供所需的数据，以证明更多的劳动密集型多维铅优化工作

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.