Development of Natural Product as Antimalarial Agent

项目描述（由申请人提供）：该项目的长期目标是开发一种价格低廉、口服有效、无毒的治疗恶性疟原虫疟疾的新药（新化学实体[NCE]）。Radix Pharmaceuticals从Nardostachys chinensis Batalin的根和根茎中分离纯化了两种天然产物。测定了两种化合物的化学结构。这些化合物对对氯喹敏感的疟疾菌株（D-6）和对氯喹耐药的疟疾菌株（W-2）均显示出同样有效的抑制活性。IC50（抑制50%的化合物浓度）优于阳性对照，氯喹和甲氟喹。这些化合物在成人肝上皮细胞和新分离的大鼠肝细胞中也显示出低毒性。此外，计算机模拟已经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，这是疟原虫不可缺少的过程。基于这些初步研究，这个I期项目的总体目标是建立候选药物的临床前概况。在第一阶段的支持下，我们将对这些化合物进行大规模的分离和纯化，并开始在啮齿动物模型中进行临床前研究，以获得毒性和功效数据。将进行以下互动研究，以高效和有效地获得啮齿动物的临床前资料：(i)将大规模分离和纯化两种天然产物（每种化合物1-2公斤）。（ii）化合物将在啮齿动物模型中进行测试，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。（三）将在感染人类疟疾菌株的免疫功能受损的BXN小鼠和感染伯氏疟原虫啮齿动物疟疾菌株的瑞士雄性白化小鼠中获得抗疟疾功效数据。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进行II期进一步开发。啮齿类动物临床前研究的成功完成将使Radix制药公司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期的工作将包括恒河猴的临床前研究（药代动力学、毒性和疗效），随后是GMP制造和GLP评估。试验性新药（IND）申请将随后提交给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.