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：
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
项目类别：
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

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贫困疾病，在全球范围内感染了超过2亿人，再加上700人一百万的风险。不稳定的情况应抗药性因此，世界卫生组织已宣布Sclared Schistosomisis是一种新疗法的疾病所需的微管（MT）是所有真核细胞中细胞骨架的重要组成部分。包括MT稳定化和 - 脱发化合物的药物形成了癌症化学疗法的基石。此外，研究建议但治疗寄生虫感染，包括相应地抗schistostostosomal行为的有利的药物样特性。苯基吡啶（PP）类，表现出明显的生物活性。最有前途的组合的关系（SARS）确定苯基吡啶（TPP）衍生物，产生有效和长期的曼森血吸虫的衍生物哺乳动物细胞中不引起MT变化或细胞毒性的复合浓度。体外结果，这些TPP作为候选抗尖锐体剂的希望。评估和开发这些化合物的下一个关键步骤作为候选治疗血吸虫病是证明一种或多种TPP念珠菌的耐受性和体内功效。我们提出了两个目标：（1）通过其设计，完整的结构活动/属性关系研究（SAR/SPR）的设计，合成和体外表型评估与S. Mansoni。分析最有希望的化合物（3-6），这些化合物符合所有预定义的选择标准血吸虫活性，选择性和“药物样”理化特性。（2）在表现最大的1-3个表现化合物的重新合成后，定义其最大耐受剂量在体内随后，在曼氏链球菌感染的小鼠模型中确定了它们的功效。支撑项目将提供体外和体内抗距离体的相关性的证据活动，并确定将来研究的一个或多个铅结构，这些结构将专门针对铅优化和对作用机理的理解。