Preclinical development of novel small molecule malaria drugs that overcome drug

描述(申请人提供)：由于抗药性寄生虫的传播，疟疾造成的全球健康问题变得更加困难。该项目启动了一个或多个候选药物(S)的临床前开发，这些候选药物来自一种创新的有效抗疟疾药物，旨在克服耐药性。我们已经开发出一种口服可用且价格低廉的新型药物，既可对抗氯喹耐药性疟疾，也可对抗氯喹敏感疟疾。一小部分精心挑选的候选药物将通过临床前测试进行推进，从而选出一种药物参加与美国食品和药物管理局(FDA)举行的新药研究前会议。在食品和药物管理局的指导下，这项工作的第二阶段将在大鼠和猴子身上进行药代动力学、药效学、药理学和毒性评估。总体目标将是完成临床前研究，从而批准用于第一阶段人体临床试验的药物的研究新药(IND)申请。 公共卫生相关性：疟疾是一种疾病，每年感染约5亿人，并导致近100万人死亡，其中大多数是儿童或孕妇。疟疾的影响正在增加，部分原因是导致疟疾的寄生虫已经进化成对目前治疗这种疾病的最好药物产生抗药性的菌株。该项目包括对旨在规避这种耐药性的新药进行临床前评估，为人类临床试验的批准铺平道路。这些候选药物在早期研究中显示出有希望的结果，并被设计为对包括孕妇和儿童在内的所有目标群体来说既便宜又安全。

DESCRIPTION (provided by applicant): The worldwide health problem created by malaria has been made more difficult by the spread of drug- resistant parasites. This project initiates preclinical development of one or more candidate(s) from an innovative new class of potent antimalarials designed to overcome drug resistance. We have developed an orally available and inexpensive class of novel drugs that act against both chloroquine-resistant and chloroquine-sensitive malaria. A small set of carefully-selected candidates will be advanced through preclinical testing, leading to the selection of a single drug for a pre-Investigational New Drug meeting with the Food and Drug Administration. With guidance from the Food and Drug Administration, pharmacokinetics, pharmacodynamics, pharmacology, and toxicity evaluations will be performed in both rats and monkeys in phase II of this work. The overall goal will be completion of preclinical studies leading to approval of the Investigative New Drug (IND) application for a drug to be used in a Phase-1 human clinical trial. PUBLIC HEALTH RELEVANCE: Malaria is a disease that infects about half a billion people annually, and kills nearly one million, most of whom are children or pregnant women. The impact of malaria is increasing, partly because the parasite that causes malaria has evolved into strains that are resistant to the best current drugs for treating the disease. This project involves preclinical evaluation of novel drugs designed to circumvent this resistance, paving the way toward approval for human clinical trials. The drug candidates show promising results in early studies, and are designed to be inexpensive as well as safe for all target groups, including pregnant women and children.