Synthesis and Evaluation of Novel Antimalarial Agents

描述（由申请人提供）：本研究的长期目标是开发安全有效的抗耐药疟疾药物。疟疾是世界上最常见的传染病之一。它影响到大约3亿人，每年导致200多万人死亡。在大多数疟疾流行地区，恶性疟原虫的多重耐药菌株的流行率不断增加，这大大降低了目前用于治疗和预防的抗疟药物的功效，因此显然需要基于新作用模式的新药剂。常山碱是从中药常山根中分离得到的一种生物碱，对恶性疟原虫有很强的抗疟活性。强烈的肝毒性使其无法用于临床治疗疟疾。在该I期研究中，将合成30种新型febrifugine类似物的集中库。预期它们保留有效的抗疟活性和期望的ADME（吸附、分布、代谢和排泄）性质。通过减少形成化学反应性和毒性中间体和代谢物的趋势，可降低肝毒性。对于功效评估，将针对两种恶性疟原虫疟疾寄生虫克隆体外测试合成的化合物：W2（对甲氟喹敏感但对氯喹、磺胺嘧啶、乙胺嘧啶和奎宁具有抗性）和D 6（对甲氟喹具有抗性但对氯喹、磺胺嘧啶、乙胺嘧啶和奎宁敏感）。对于毒理学研究，将在成人肝上皮细胞和小鼠乳腺肿瘤细胞中检测这些化合物。具体目标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II期研究中，将大规模合成具有所需选择性的化合物，并通过在啮齿动物和灵长类动物模型中测试这些化合物以获得疗效、ADME和毒性数据来开始临床前试验。然后，将向FDA提交研究性新药（IND）申请。

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.