Preclinical Studies of Natural Product Derivatives as Antimalarial Agents

天然产物衍生物作为抗疟药的临床前研究

• 批准号: 8220795
• 负责人: Shuren Zhu
• 金额: $ 45.07万
• 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: 2008-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220795
• 关键词: Affect; Africa; Aminopeptidase; Antimalarials; 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; 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; 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; inhibitor/antagonist; killings; meetings; micronucleus; multidisciplinary; novel; novel therapeutics; pre-clinical; preclinical study; prevent; public health relevance; resistant strain; scale up

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.

描述（由申请人提供）：该项目着重于开发用于预防和治疗恶性疟原虫疟疾的新型治疗剂。在啮齿动物模型中，一项为期两年的I期研究发现了具有有效的抗疟疾活性和抗抗性疟疾菌株的新分子。铅化合物的毒性低，具有高口服生物利用度和其他理想的ADMET特性。抗性发展的潜力被证实很小，还建立了可扩展的化学合成。在与FDA进行预先会议之后，设计了拟议的SBIR II期研究。在第二阶段的支持下，我们将执行：（i）扩展合成两种铅化合物和一种用于GLP毒性研究的化合物的CGMP制造； （ii）猴子中的范围调查毒性和药代动力学； （iii）猴子重复剂量毒性； （iv）感染了恶性疟原虫的Aotus猴子中的抗性活性； （v）GLP毒理学研究：具有毒性，功能观测电池和微核评估的28天毒性研究。 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2.5亿人，每年导致1-3万人死亡。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。

项目成果

Febrifugine analogue compounds: synthesis and antimalarial evaluation.

• DOI: 10.1016/j.bmc.2011.11.053
• 发表时间: 2012-01-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Zhu, Shuren;Chandrashekar, Gudise;Meng, Li;Robinson, Katie;Chatterji, Dipsanker
• 通讯作者: Chatterji, Dipsanker