Development of Small Molecules as Antiprotozoal Agents

小分子抗原虫剂的开发

• 批准号: 8390072
• 负责人: Shuren Zhu
• 金额: $ 49.05万
• 依托单位: RADIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8390072
• 关键词: Affect; Africa; Aminopeptidase; Antimalarials; Antiprotozoal Agents; Aotus primate; Area; Biological Availability; Biological Factors; Cessation of life; Clinical; Collaborations; Communicable Diseases; Country; Cyclic GMP; Data; Development; Disease; Dose; Drug Kinetics; Evaluation; Falciparum Malaria; Generations; Goals; Growth; In Vitro; Institution; Investigational Drugs; Investigational New Drug Application; Lead; Legal patent; Malaria; Maximum Tolerated Dose; Modeling; Molecular; Monkeys; Multi-Drug Resistance; No-Observed-Adverse-Effect Level; Oral; Outcome; Parasites; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasmodium falciparum; Prevalence; Prevention; Primates; Property; Prophylactic treatment; Research; Resistance; Resistance development; Rodent Model; Small Business Innovation Research Grant; South America; Southeastern Asia; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Toxic effect; Toxicokinetics; Toxicology; chemical synthesis; chemotherapy; design; drug candidate; drug development; drug discovery; hemozoin; in vivo Model; inhibitor/antagonist; killings; meetings; micronucleus; multidisciplinary; novel; novel therapeutics; pre-clinical; prevent; resistant strain; scale up; small molecule

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.

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药物。先前的一个I期项目已经在一些体外和体内模型中发现了对敏感和多药耐药疟疾菌株具有强效抗疟活性的新分子。铅化合物毒性低，口服生物利用度高。已证实产生耐药性的可能性很小，还建立了可扩展的化学合成。目前的SBIR II期研究是在与FDA举行IND前会议后设计的。在第二阶段的支持下，将大规模合成这两种先导化合物。将在猴模型中进行剂量范围探索毒性、重复给药毒性和药代动力学研究。将在感染恶性疟原虫的Aotus猴中评价抗疟疗效。将选择一种具有所需毒性、功效和药代动力学性质的化合物用于cGMP生产。然后将对该化合物进行GLP毒理学研究：确定性28天毒性研究，包括毒代动力学、功能观察组合和微核评价。研究性新药（IND）申请将在II期研究结束时向FDA提交。该项目的新奇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，但已组装的多学科团队和多机构合作将加速临床候选药物的产生。 公共卫生相关性：疟疾是世界上最常见的传染病之一。它影响到大约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率日益增加，大大降低了目前用于预防和治疗这种疾病的抗疟药物的效力。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。这项研究的新奇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速临床候选人的产生。