Development of Small Molecules as Antiprotozoal Agents

描述(由申请人提供)：拟议的研究重点是开发用于预防和治疗恶性疟原虫引起的疟疾的新型治疗剂。之前的一个第一阶段项目已经在一些体外和体内模型中发现了具有强大抗疟疾活性的新分子，对敏感和多药耐药的疟疾菌株都具有抗疟疾活性。先导化合物毒性低，口服生物利用度高。抗药性的发展潜力被证实是很小的，并建立了可扩展的化学合成。目前的SBIR第二阶段研究是在IND前与FDA举行会议后设计的。在第二阶段的支持下，将大规模合成这两种先导化合物。测程毒性、重复剂量毒性和药代动力学研究将在猴子模型中进行。将评估感染恶性疟原虫的Aotus猴子的抗疟疾效果。将选择一种具有预期毒性、有效性和药代动力学特性的化合物用于cGMP生产。然后，该化合物将接受GLP毒理学研究：最终的28天毒性研究，包括毒代动力学、功能观察、电池和微核评估。研究新药(IND)申请将在第二阶段研究结束时提交给FDA。该项目的新奇之处在于发现了新的分子实体。该项目涉及药物开发的标准方法，但已经组建的多学科团队和多机构合作将加快临床候选人的产生。 与公共卫生相关：疟疾是世界上最常见的传染病之一。它影响了大约2.25亿人，每年导致大约791,000人死亡。在大多数疟疾流行地区，多重耐药菌株的流行日益增加，大大降低了目前用于预防和治疗这一疾病的抗疟疾药物的效力。该项目的重点是开发一种新的防治恶性疟原虫的治疗剂。这项研究的新颖性在于发现了新的分子实体。已经组建的多学科团队和多机构合作将加快临床候选人的产生。

DESCRIPTION (provided by applicant): The proposed research focuses on the development of novel therapeutic agents for the prevention and treatment of malaria caused by P. falciparum. A previous Phase I project has discovered novel molecules with potent antimalarial activity against both sensitive and multidrug resistant malaria strains in some in vitro and in vivo models. Lead compounds are low in toxicity and possess high oral bioavailability. The potential for development of resistance was confirmed to be small and a scalable chemical synthesis was also established. The current SBIR Phase II research was designed after pre-IND meeting with FDA. Under Phase II support, the two lead compounds will be synthesized on a large scale. Range-finding toxicity, repeat dose toxicity, and pharmacokinetic studies will be conducted in monkey models. Antimalarial efficacy will be evaluated in Aotus monkeys infected with P. falciparum. One compound with desired toxicity, efficacy, and pharmacokinetic properties will be selected for cGMP manufacturing. This compound will then undergo GLP toxicology studies: definitive 28-day toxicity study with toxicokinetic, functional observations battery and micronucleus evaluations. An investigational new drug (IND) application will be filed with FDA at the end of Phase II research. The novelty of the project is the discovery of new molecular entities. The project involves standard approaches to drug development, but the multidisciplinary team and multi- institution collaboration that has been assembled will accelerate the generation of clinical candidates. PUBLIC HEALTH RELEVANCE: Malaria is one of the most common infectious diseases in the world. It affects approximately 225 million people and leads to about 791,000 death a year. The increasing prevalence of multiple drug resistant strains in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for prophylaxis and treatment of this disease. This project focuses on the development of a novel therapeutic agent for preventing and treating P. falciparum malaria. The novelty of the research is the discovery of new molecular entities. The multidisciplinary team and multi-institution collaboration that has been assembled will accelerate the generation of clinical candidates.