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.

项目描述（由申请人提供）：本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I期研究发现了新的分子，这些分子对啮齿动物模型中的敏感和耐药疟疾菌株都具有强效抗疟活性。先导化合物毒性低，具有较高的口服生物利用度和其他理想的ADMET特性。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。在与FDA召开IND前会议后，设计了拟议的SBIR II期研究。在II期支持下，我们将进行：（I）两种先导化合物的规模化合成和一种化合物的cGMP生产，用于GLP毒性研究;（II）猴的剂量范围探索毒性和药代动力学;（III）猴的重复给药毒性;（IV）感染恶性疟原虫的Aotus猴的抗疟活性;（V）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。 公共卫生相关性：疟疾是世界上最常见的传染病之一。它影响大约2.5亿人，每年导致1-3百万人死亡。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。

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