Development of thiophen-2-yl-phenylpyrimidines for treatment of schistosomiasis

噻吩-2-基-苯基嘧啶治疗血吸虫病的研制

• 批准号: 10371822
• 负责人: Carlo Ballatore
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371822
• 关键词: Adolescent; Adult; Antiparasitic Agents; Biological Assay; Cell Maintenance; Cell Shape; Cell division; Chemicals; Chemotherapy-Oncologic Procedure; Cytoskeleton; Data; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Eukaryotic Cell; Evaluation; Exhibits; Funding; Future; Hepatic; In Vitro; Infection; Intracellular Transport; Laboratories; Lead; Letters; Libraries; Light; Mammalian Cell; Maximum Tolerated Dose; Measures; Methods; Microtubule Stabilization; Microtubule stabilizing agent; Microtubules; Mus; National Institute of Allergy and Infectious Disease; Neurodegenerative Disorders; Paralysed; Parasitic infection; Pharmaceutical Preparations; Phenotype; Plasma; Poverty; Praziquantel; Procedures; Property; Refractory; Research; Research Proposals; Risk; Schedule; Schistosoma; Schistosoma mansoni; Schistosome Parasite; Schistosomiasis; Selection Criteria; Series; Structure; Structure-Activity Relationship; Testing; Therapeutic; TimeLine; Trypanosoma brucei brucei; United States National Institutes of Health; World Health Organization; analog; base; cell growth; cell motility; cytotoxicity; design; disorder control; drug development; drug discovery; efficacy study; egg; follow-up; in vitro activity; in vivo; lead optimization; member; mouse model; multidisciplinary; novel; novel therapeutics; programs; standard of care

ABSTRACT Schistosomiasis is a disease of poverty that infects over 200 million people worldwide and places another 700 million at risk. Current treatment and control of the disease rely on just one drug, praziquantel (PZQ) - a precarious situation should drug resistance emerge. Furthermore, the therapeutic profile of PZQ is not ideal. The World Health Organization has therefore declared schistosomiasis a disease for which new therapies are urgently needed. Microtubules (MTs) are essential components of the cytoskeleton in all eukaryotic cells. MT-targeting drugs, which include MT-stabilizing and -destabilizing compounds, form a cornerstone of cancer chemotherapy; in addition, studies suggest that such compounds may be useful to treat parasitic infections, including schistosomiasis. Accordingly, we phenotypically screened a library of >300 MT-stabilizing agents with generally favorable drug-like properties for anti-schistosomal activity. We identified different members of the phenylpyrimidine (PP) class that exhibited marked bioactivity. Further exploration of the structure activity relationships (SARs) of the most promising compounds identified a series of novel thiophen-2-yl- phenylpyrimidine (TPP) derivatives that produce a potent and long-lasting paralysis of Schistosoma mansoni at compound concentrations that do not elicit MT changes or cytotoxicity in mammalian cells. In light of these in vitro results, these TPPs hold promise as candidate anti-schistosomal agents. The next critical step in the evaluation and development of these compounds as candidate treatments for schistosomiasis is to demonstrate the tolerability and in vivo efficacy of one or more TPP candidates. Towards this end, we propose two aims: (1) Complete structure activity/property relationship studies (SAR/SPR) of 30-50 TPPs through their design, synthesis and in vitro phenotypic evaluation vs. S. mansoni. This will be followed up with pharmacokinetic (PK) analysis of the most promising compounds (3–6) that meet all pre-defined selection criteria for in vitro anti- schistosomal activity, selectivity and “drug-like” physicochemical properties. (2) After the resynthesis of the top 1-3 performing compounds, define their maximum tolerated doses in vivo and subsequently determine their efficacy in a mouse model of S. mansoni infection. The proposed project will provide evidence of a correlation between in vitro and in vivo anti-schistosomal activity, and identify one or more lead structures for future studies that will focus specifically on lead optimization and an understanding of the mechanism of action.

摘要 血吸虫病是一种贫困疾病，感染着全球2亿多人，另有700人 数百万人处于危险之中。目前这种疾病的治疗和控制仅依靠一种药物，吡喹酮(PZQ)-a 如果出现抗药性，情况可能会变得不稳定。此外，PZQ的治疗方案并不理想。这个 因此，世界卫生组织宣布血吸虫病是一种迫切需要新疗法的疾病 需要的。微管是所有真核细胞中细胞骨架的重要组成部分。MT-目标定位 药物，包括稳定MT和破坏稳定的化合物，构成了癌症化疗的基石； 此外，研究表明，这种化合物可能有助于治疗寄生虫感染，包括 血吸虫病。因此，我们对&gt；300 MT稳定剂的文库进行了表型筛选 具有良好的抗血吸虫活性的类药物性质。我们确定了不同的成员 苯基嘧啶(PP)类化合物，具有显著的生物活性。对构造活动性的进一步探讨 最有希望的化合物的关系(SARS)确定了一系列新的噻吩基-2-基- 苯基嘧啶(TPP)衍生物，可使曼氏血吸虫在 在哺乳动物细胞中不会引起MT变化或细胞毒性的化合物浓度。根据这些情况，在 体外结果显示，这些TPP有望成为抗血吸虫药物的候选药物。 评估和开发这些化合物作为候选治疗药物的下一个关键步骤 血吸虫病是为了证明一个或多个候选TPP的耐受性和体内疗效。朝向 为此，我们提出了两个目标： (1)通过设计完成30-50个TPP的结构活性/性质关系研究(SAR/SPR)； 曼氏沙门氏菌的合成及体外表型评价。这将通过药物动力学(PK)进行后续研究 分析最有希望的化合物(3-6)，满足所有预定义的体外抗肿瘤筛选标准 血吸虫活性、选择性和“类药物”的物理化学性质。 (2)在前1-3个执行化合物的重新合成后，确定它们在体内的最大耐受量 并随后在曼氏葡萄球菌感染的小鼠模型中确定它们的疗效。 拟议的项目将提供体外和体内抗血吸虫之间相关性的证据。 活动，并为未来的研究确定一个或多个铅结构，这些结构将专门关注铅 优化和对作用机制的理解。