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

基本信息

批准号：
10494250
负责人：
Carlo Ballatore
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10494250
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 Persons 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

项目摘要

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.

抽象的血吸虫病是一种导致贫困的疾病，感染了全世界 2 亿多人，并导致另外 700 人死亡。目前该疾病的治疗和控制仅依靠一种药物，即吡喹酮 (PZQ)——一种如果出现耐药性，情况将变得不稳定。此外，PZQ 的治疗效果并不理想。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微管 (MT) 是所有 MT 靶向细胞的细胞骨架的重要组成部分。药物，包括 MT 稳定和不稳定化合物，构成癌症化疗的基石；此外，研究表明此类化合物可能有助于治疗寄生虫感染，包括因此，我们通过表型筛选了超过 300 种 MT 稳定剂的库。我们确定了具有抗血吸虫活性的良好药物样特性。具有显着生物活性的苯基嘧啶（PP）类的结构活性的进一步探索。最有前途的化合物的关系（SAR）确定了一系列新型噻吩-2-基- 苯基嘧啶 (TPP) 衍生物，可对曼氏血吸虫产生有效且持久的麻痹作用鉴于这些，化合物浓度不会引起哺乳动物细胞的 MT 变化或细胞毒性。体外结果显示，这些 TPP 有希望作为候选抗血吸虫药物。评估和开发这些化合物作为候选治疗方法的下一个关键步骤血吸虫病的目的是证明一种或多种 TPP 候选药物的耐受性和体内功效。为此，我们提出两个目标： (1) 通过设计完成 30-50 个 TPP 的结构活性/性能关系研究 (SAR/SPR)，与曼氏沙门氏菌的合成和体外表型评估随后将进行药代动力学 (PK)。分析最有前途的化合物 (3-6)，这些化合物符合所有预先定义的体外抗肿瘤选择标准血吸虫活性、选择性和“类药物”理化特性。 (2) 重新合成性能最好的1-3个化合物后，确定它们的体内最大耐受剂量并随后确定它们在曼氏沙门氏菌感染小鼠模型中的功效。拟议的项目将提供体外和体内抗血吸虫药物之间相关性的证据活动，并为未来的研究确定一个或多个先导结构，这些结构将专门关注先导结构优化并了解作用机制。