Preclinical Studies of Natural Product Derivatives as Antimalarial Agents

描述(申请人提供)：该项目的重点是开发一种用于预防和治疗恶性疟原虫疟疾的新型治疗剂。一项为期两年的第一阶段研究在啮齿动物模型中发现了具有强大抗疟疾活性的新分子，对敏感和耐药疟疾株都具有抗疟疾活性。先导化合物毒性低，具有高的口服生物利用度和其他理想的ADMET特性。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。在IND前与FDA举行会议后，设计了拟议的SBIR第二阶段研究。在第二阶段的支持下，我们将进行：(I)扩大合成两种先导化合物和制造一种用于GLP毒性研究的化合物；(Ii)在猴子中的测程毒性和药代动力学；(Iii)对猴子的重复剂量毒性；(Iv)对感染恶性疟原虫的Aotus猴的抗疟疾活性；(V)GLP毒理学研究：通过毒代动力学、功能观察和微核评估，对GLP进行为期28天的最终毒性研究。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2.5亿人，每年导致100-300万人死亡。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): This project focuses on the development of a novel therapeutic agent for preventing and treating P. falciparum malaria. A two-year Phase I research has discovered novel molecules with potent antimalarial activity against both sensitive and resistant malaria strains in rodent models. Lead compounds are low in toxicity and possess high oral bioavailability and other ideal ADMET properties. The potential for development of resistance was confirmed to be small and a scalable chemical synthesis was also established. After pre-IND meeting with FDA, the proposed SBIR Phase II research was designed. Under Phase II support, we will perform: (I) Scale up synthesis of two lead compounds and cGMP manufacturing of one compound for GLP toxicity studies; (II) Range-finding toxicity and pharmacokinetics in monkeys; (III) Repeat dose toxicity in monkeys; (IV) Antimalarial activity in Aotus monkeys infected with P. falciparum; (V) 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 250 million people and leads to 1-3 million 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.