Development of Natural Product as Antimalarial Agent

描述（由申请人提供）：本项目的长期目标是开发一种廉价、口服活性、无毒且可治愈恶性疟原虫疟疾的新药（新化学实体[NCE]）。Radix Pharmaceuticals从甘松的根和根茎中分离纯化了两种天然产物。确定了两种化合物的化学结构。这些化合物对氯喹敏感疟疾株（D-6）和氯喹抗性疟疾株（W-2）显示出同等有效的抑制活性。IC 50（提供50%抑制的化合物浓度）上级于阳性对照氯喹和甲氟喹。这些化合物在成人肝上皮细胞和新鲜分离的大鼠肝细胞中也显示出低毒性。此外，计算机模拟已证实，这些化合物具有理想的ADME（吸附，分布，代谢和排泄）特性和良好的口服生物利用度。这些化合物具有干扰疟原虫色素合成的潜力，而疟原虫色素合成是疟疾寄生虫不可或缺的过程。基于这些初步研究，该I期项目的总体目标是为候选人建立临床前特征。在第一阶段的支持下，我们将进行这些化合物的放大分离和纯化，并开始在啮齿动物模型中进行临床前研究，以获得毒性和疗效数据。将进行以下互动研究，以高效和有效地获得啮齿动物临床前特征：（i）将以更大规模（每种化合物1-2公斤）分离和纯化两种天然产物。(ii)将在啮齿动物模型中测试化合物，以获得急性和亚急性毒性、胎儿毒性、厌食毒性和神经毒性信息。(iii)将在感染人疟疾菌株的免疫受损BXN小鼠和感染啮齿类疟疾菌株伯氏疟原虫的雄性瑞士白化病小鼠中获得抗疟疗效数据。在I期研究完成后，将选择具有口服活性且具有良好治疗指数的化合物用于II期的进一步开发。啮齿动物临床前研究的成功完成将使Radix Pharmaceuticals能够筹集额外的资金，并吸引商业合作伙伴将候选药物推向临床阶段。II期的工作将包括在恒河猴中进行临床前研究（药代动力学、毒性和疗效），然后进行GMP生产和GLP评价。研究性新药（IND）申请将提交给FDA。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a new drug (new chemical entity [NCE]) that is inexpensive, orally active, non-toxic and can provide cure for P. falciparum malaria. Radix Pharmaceuticals has isolated and purified two natural products from the roots and rhizomes of Nardostachys chinensis Batalin. The chemical structures of both compounds were determined. These compounds showed equally potent inhibitory activity against both chloroquine sensitive malaria strain (D-6) and chloroquine resistant malaria strain (W-2). The IC50's (concentration of compound that affords 50% of inhibition) were superior to the positive controls, chloroquine and mefloquine. These compounds also demonstrated low toxicity in human adult liver epithelial cells and freshly isolated rat hepatocytes. Additionally, in silico modeling has confirmed that these compounds possess desirable ADME (adsorption, distribution, metabolism, and excretion) characteristics and good oral bioavailability. These compounds possess the potential to interfere hemozoin synthesis, an indispensable process for the malaria parasite. Based on these preliminary studies, the overall goal of this Phase I project is to establish pre-clinical profiles for the candidates. Under Phase I support, we will perform the scale up isolation and purification of these compounds and begin pre-clinical studies in rodent models to obtain toxicity and efficacy data. The following interactive studies will be performed to obtain rodent pre-clinical profiles efficiently and effectively: (i) The two natural products will be isolated and purified in a larger scale (1-2 kg per compound). (ii) Compounds will be tested in rodent models to obtain acute and sub-acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. (iii) Antimalarial efficacy data will be obtained in immunocompromised BXN mice infected with human malaria strains and male Swiss albino mice infected with rodent malaria strain P. berghei. On completion of the Phase I studies, compound(s) that are orally active and possess good therapeutic index will be selected for further development in Phase II. The successful completion of rodent pre-clinical studies will enable Radix Pharmaceuticals to raise additional funding and attract a commercial partner to push the drug candidate to clinical stage. The efforts in Phase II would include pre-clinical studies (pharmacokinetics, toxicity, and efficacy) in Rhesus monkey, followed by GMP manufacturing and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA.