Optimization of Antischistosomal Chemotypes

 描述（由申请人提供）：血吸虫病是一种热带寄生虫病，由血吸虫属吸虫感染引起，影响全球多达4.4亿人，其中7.79亿人面临感染风险。一种治疗血吸虫病的新药亟待开发 由于吡喹酮目前是最后的药物，抗药性的发展不容忽视，特别是鉴于其在许多地方流行病中的大规模使用。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，具有抗所有寄生虫阶段的活性和新的作用机制。本提案的目的是确定一种或多种抗组胺药物开发候选药物。为了实现这一目标，我们将优化四个有前途的抗溶酶体化学型-臭氧，芳基乙内酰脲，脲羧酸，和N，N '-二芳基脲。我们提出四个具体目标：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）启动优化目标化合物的作用机制（MOA）研究。化合物设计将以现有SAR为依据，并在前瞻性计算机物理化学分析的指导下最大限度地提高结构多样性。基于理化分析、体外ADME和细胞毒性（SA 1）、离体和体内抗溶酶体活性以及体内ADME（SA 2和3）的迭代反馈，将出现新的结构假设，我们将合成其他靶化合物。目标化合物将通过使用明确定义的进展标准的各种测定而进展。我们认为，这项研究是创新的几个原因。首先，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溶酶体功效，但具有非常低的离体（体内）活性至无活性，这与先导化合物的通常情况相反， 具有体外活性但没有体内活性。因此，这些化学型的机制调查可能会导致新的治疗方法/药物靶点血吸虫病。其次，对于芳基乙内酰脲，我们概述了一种设计策略，以减少抗雄激素的副作用，利用负SAR数据收集雄激素受体（AR）配体结合研究，减少，而不是增加，AR结合亲和力。这项工作的预期结果是确定一种或多种有效对抗所有寄生虫阶段并具有新作用机制的抗寄生虫体药物开发候选物。这项拟议中的研究意义重大，因为一种新药在耐药血吸虫病的化疗中将是重要的，并且可能在遏制这种寄生虫病的综合控制计划中有价值。

 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.