Development of Small Molecules as Antiprotozoal Agents

项目描述（由申请人提供）：拟研究的重点是开发预防和治疗恶性疟原虫引起的疟疾的新型治疗剂。先前的一期项目在一些体外和体内模型中发现了对敏感和耐多药疟疾菌株具有有效抗疟活性的新分子。铅化合物毒性低，口服生物利用度高。经证实，发展耐药性的潜力很小，并建立了可扩展的化学合成方法。目前的SBIR II期研究是在与FDA进行ind前会议后设计的。在第二阶段的支持下，这两种先导化合物将大规模合成。将在猴子模型中进行测距毒性、重复剂量毒性和药代动力学研究。将对感染恶性疟原虫的猕猴进行抗疟效果评价。将选择一种具有理想毒性、有效性和药代动力学性质的化合物进行cGMP生产。然后，该化合物将进行GLP毒理学研究：确定的28天毒性研究，包括毒性动力学、功能观察、电池和微核评估。研究新药（IND）申请将在II期研究结束时提交给FDA。这个项目的新颖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，但已组建的多学科团队和多机构合作将加速临床候选药物的产生。

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.