Synthesis and Evaluation of Novel Antimalarial Agents

新型抗疟药物的合成与评价

• 批准号: 6874075
• 负责人: Shuren Zhu
• 金额: $ 10万
• 依托单位: RADIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874075
• 关键词: Plasmodium falciparum; alkaloids; antimalarial agents; cell line; combinatorial chemistry; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; hepatotoxin; liver cells; malaria; microorganism disease chemotherapy; multidrug resistance; piperidine; quinazolines

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop drugs that are safe and effective against drug-resistant malaria. Malaria is one of the most common infectious diseases in the world. It affects approximately 300 million people and leads to more than 2 million death a year. The increasing prevalence of multiple drug resistant strains of Plasmodium falciparum in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for both treatment and prophylaxis and there is a clear need for new medicinal agents based on novel mode of action. Febrifugine is an alkaloid isolated from roots of Dichroa febrifuga Lour and showed powerful antimalarial activity against P. falciparum. Strong liver toxicity has precluded its clinical use against malaria. In this Phase I study, a focused library of thirty novel febrifugine analogues will be synthesized. They are expected to retain the potent antimalarial activity and desirable ADME (adsorption, distribution, metabolism, and excretion) properties. Lower liver toxicity will be achieved by reducing the tendency to form chemically reactive and toxic intermediates and metabolites. For efficacy evaluation, synthesized compounds will be tested in vitro against two P. falciparum malaria parasite clones: W2 (susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, and quinine) and D6 (resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine and quinine). For toxicological studies, these compounds will be tested in human adult liver epithelial cells and mouse mammary tumor cells. The specific aim would be the discovery of some less toxic yet still potent compounds whose selectivity (defined as toxicity/anti-malarial activity) equals or greater than 1000. In Phase II study, compounds with desirable selectivity will be synthesized in a large scale and pre-clinical trials will begin by testing these compounds in rodent and primate models to obtain efficacy, ADME and toxicity data. An investigational new drug (IND) application will then be filed with FDA.

描述(申请人提供)：这项研究的长期目标是开发安全有效的药物来对抗抗药性疟疾。疟疾是世界上最常见的传染病之一。它影响了大约3亿人，每年导致200多万人死亡。恶性疟原虫多重耐药株在大多数疟疾流行地区日益流行，大大降低了当前抗疟疾药物的治疗和预防效果，显然需要基于新的作用模式的新的药物。赤潮藤碱是从毛地黄根部分离得到的一种生物碱，对恶性疟原虫有很强的抗疟活性。强烈的肝脏毒性使其无法在临床上用于治疗疟疾。在这项第一阶段的研究中，将合成一个包含30个新的苯呋喃类似物的集中文库。它们有望保持强大的抗疟疾活性和理想的ADME(吸附、分布、代谢和排泄)特性。通过减少形成化学反应和有毒中间体和代谢物的倾向，将实现较低的肝脏毒性。为了评估疗效，合成的化合物将在体外测试两个恶性疟原虫克隆：W2(对甲氟喹敏感，但对氯喹、磺胺多辛、乙胺嘧啶和奎宁耐药)和D6(对甲氟喹耐药，但对氯喹、磺胺多辛、乙胺四胺和奎宁敏感)。为了进行毒理学研究，这些化合物将在人类成年肝上皮细胞和小鼠乳腺肿瘤细胞中进行测试。具体目标将是发现一些毒性较小但仍然有效的化合物，其选择性(定义为毒性/抗疟疾活性)等于或大于1000。在第二阶段研究中，将大规模合成具有理想选择性的化合物，临床前试验将通过在啮齿动物和灵长类动物模型中测试这些化合物来获得疗效、ADME和毒性数据。然后将向FDA提交研究用新药(IND)申请。