Preclinical Studies of Natural Product Derivatives as Antimalarial Agents

项目描述（申请人提供）：本项目主要研究一种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对敏感和耐药疟疾菌株具有有效抗疟疾活性的新分子。铅化合物毒性低，具有较高的口服生物利用度和其他理想的ADMET特性。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。在与FDA进行ind前会议后，设计了拟议的SBIR II期研究。在第二阶段的支持下，我们将进行：(1)扩大两种先导化合物的合成和一种化合物的cGMP生产，用于GLP毒性研究；（II）猴子的测距毒性和药代动力学；（三）猴子重复剂量毒性；（四）感染恶性疟原虫的猕猴抗疟活性；(V) 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，但已经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): 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.