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。它每年影响约3亿人，导致200多万人死亡。恶性疟原虫多重耐药菌株在大多数疟疾流行地区的日益流行，大大降低了目前抗疟药物的治疗和预防功效，显然需要基于新作用方式的新药。白蚁碱是从白蚁根中分离得到的一种生物碱，对恶性疟原虫具有很强的抗疟活性。强烈的肝毒性使其无法用于临床治疗疟疾。在第一阶段的研究中，将合成30种新型发热嘌呤类似物的重点文库。它们有望保留有效的抗疟活性和理想的ADME（吸附、分布、代谢和排泄）特性。降低肝毒性将通过减少形成化学反应性和毒性中间体和代谢物的倾向来实现。为评价疗效，将在体外对两种恶性疟原虫克隆进行试验：W2（对甲氟喹敏感，但对氯喹、磺胺多辛、乙胺多辛和奎宁耐药）和D6（对甲氟喹耐药，但对氯喹、磺胺多辛、乙胺多辛和奎宁敏感）。为了进行毒理学研究，这些化合物将在成人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II期研究中，具有理想选择性的化合物将被大规模合成，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功效、ADME和毒性数据。然后将向FDA提交一份研究性新药（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.