Validation of New Antimalarial Leads

新抗疟药物的验证

• 批准号: 7984921
• 负责人: Rodney Kiplin Guy
• 金额: $ 123.89万
• 依托单位: MEDICINES FOR MALARIA VENTURE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984921
• 关键词: Adsorption; Antimalarials; Applications Grants; Chemicals; Child; Chloroquine; Clinical; Development; Disease; Drug resistance; Erythrocytes; Excretory function; Funding; Goals; Growth; Health; Hospitals; Human; Infection; Lead; Malaria; Metabolism; Morbidity - disease rate; Pharmaceutical Preparations; Phase; Plasmodium; Plasmodium falciparum; Property; Research; Resistance; Series; Solutions; Staging; Structure; Structure-Activity Relationship; United States National Institutes of Health; Validation; Work; base; candidate selection; drug candidate; drug development; high throughput screening; inhibitor/antagonist; meetings; novel; pre-clinical; programs; public health relevance; scaffold

DESCRIPTION (provided by applicant): This grant application focuses on hit-to-lead studies that will evaluate a series of hits arising from a cellular high throughput screen that detected inhibitors of Plasmodium falciparum growth in the intra-erythrocytic stages. For each novel hit series, we will explore structure activity relationships that govern potency, cellular selectivity, and efficacy; structure property relationships that govern adsorption, distribution, metabolism, and excretion; and mechanism of action. In each case, the purpose of the studies is to evaluate the potential for the development of each novel series in the context of the existing portfolio of antimalarial drugs and development candidates. The series will be prioritized based upon these studies with the ideal series having novel mechanism of action, high inherent selectivity for Plasmodium versus the human host, and physiochemical properties that are compatible with development of an orally available drug candidate. As such, the project is a perfect adjunct to ongoing MMV support of lead-candidate development as it will provide a pipeline of new inhibitor types for further development. The specific aims of this program are: 1. To validate by re-synthesis and limited structure activity relationship studies as many hits as possible from the SJCRH screen. 2. To execute hit-to-lead studies on at least 5 validated hits, either progressing them to early lead status or disqualifying them from further work. 3. To assess liabilities for each early lead and develop specific plans for their later development. Public Health Relevance: Malaria is one of the most profound existing human health problems with annual morbidity of several hundred million cases worldwide. Although drugs remain the dominant means for treating malaria infections, both prophylactically and curatively, inexpensive, effective drugs such as chloroquine now suffer from worldwide resistance. The development of multiple novel antimalarial chemotypes is the strategy that offers the most promise for circumventing drug resistant malaria in the campaign for disease eradication.

描述（由申请人提供）：本拨款申请重点关注从命中到先导的研究，该研究将评估细胞高通量筛选产生的一系列命中，该筛选检测红细胞内阶段恶性疟原虫生长的抑制剂。对于每个热门小说系列，我们将探索控制效力、细胞选择性和功效的结构活性关系；控制吸附、分布、代谢和排泄的结构特性关系；和作用机制。在每种情况下，研究的目的都是在现有的抗疟药物和候选药物组合的背景下评估每个小说系列的开发潜力。该系列将根据这些研究进行优先排序，理想的系列具有新颖的作用机制、对疟原虫相对于人类宿主的高固有选择性以及与口服候选药物的开发相容的理化特性。因此，该项目是 MMV 对先导候选药物开发持续支持的完美补充，因为它将提供一系列新抑制剂类型以供进一步开发。该计划的具体目标是： 1. 通过重新合成和有限的结构活性关系研究来验证来自 SJCRH 屏幕的尽可能多的命中。 2. 对至少 5 个已验证的命中进行从命中到先导的研究，要么将它们推进到早期先导状态，要么取消它们进一步工作的资格。 3. 评估每个早期线索的责任并为其后期发展制定具体计划。 公共卫生相关性：疟疾是现有最严重的人类健康问题之一，全世界每年发病数亿例。尽管药物仍然是治疗疟疾感染的主要手段，无论是预防性还是治疗性，但氯喹等廉价、有效的药物现在在世界范围内遭受耐药性。开发多种新型抗疟化学型是在根除疾病运动中最有希望规避耐药性疟疾的策略。