Development of Small Molecules as Antiprotozoal Agents

小分子抗原虫剂的开发

基本信息

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
项目类别：
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

项目摘要

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剂。先前的I期项目在某些体外和体内模型中发现了具有有效抗疟疾活性的新型分子，具有有效的抗疟疾活性。铅化合物的毒性低，并且具有高口服生物利用度。抗性发展的潜力被证实很小，还建立了可扩展的化学合成。当前的SBIR II期研究是在与FDA预先会议之前设计的。在II期支持下，将大规模合成两种铅化合物。在猴子模型中将进行范围调查毒性，重复剂量毒性和药代动力学研究。将在感染恶性疟原虫的Aotus猴子中评估抗疟疾功效。将选择一种具有所需毒性，功效和药代动力学特性的化合物进行CGMP制造。然后，该化合物将接受GLP毒理学研究：具有毒性，功能观察的最终28天毒性研究，电池和微核评估。 II阶段研究结束时，将向FDA提出研究新药（IND）。该项目的新颖性是发现了新分子实体。该项目涉及药物开发的标准方法，但是组装的多学科团队和多机构合作将加速临床候选者的产生。公共卫生相关性：疟疾是世界上最常见的传染病之一。它影响约2.25亿人，每年导致约791,000人死亡。在大多数疟疾流行地区，多种药物抗性菌株的患病率的增加显着降低了当前抗疟药对预防和治疗该疾病的疗效。该项目的重点是开发用于预防和治疗恶性疟原虫疟疾的新型治疗剂。这项研究的新颖性是发现新分子实体。组装的多学科团队和多机构合作将加速临床候选人的产生。