Pre-Clinical Development of Natural Product Analogues as Antimalarial Agents

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]）。SBIR I期研究和Radix Pharmaceuticals的额外工作表明，一些新型的febrifugine类似物在低纳摩尔浓度下是体外敏感和多药耐药人疟疾菌株的有效抑制剂。这些化合物具有新的作用模式，通过损害滋养体阶段寄生虫成熟所需的血珠蛋白形成。合成的化合物在人成人肝上皮细胞和新鲜分离的大鼠肝细胞中表现出低毒性。未观察到体外心脏毒性或遗传毒性。已经建立了制备用于PK研究的放射性[3 H]化合物的可扩展的合成路线。已获得FDA关于必要的正在进行的临床前研究的建议，以保证研究性新药（IND）提交。在成功完成可行性研究的基础上，该第二阶段项目的总体目标是为候选人建立详细的临床前档案。在II期研究的支持下，我们将进行这些化合物的放大合成，并开始在动物模型中进行临床前研究，以获得毒性、药代动力学和疗效数据。将进行以下交互式研究，以高效和有效地获得啮齿动物临床前特征：（i）将以较大规模（每种化合物2-3 kg）合成I期研究中确定的六种化合物，用于功效和毒性研究，并以放射性[3 H]形式（每种化合物100 mg）合成药物动力学研究。(ii)将在啮齿动物模型中测试供试化合物，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)将向大鼠和小鼠腹膜内、皮下或经口施用测试化合物，并计算药代动力学参数。(iv)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。这些临床前研究将明确验证候选药物作为治疗急性疟疾的理想新药的潜力。II期研究完成后，将选择一种或两种具有口服活性并具有良好生物利用度和治疗指数的化合物进行进一步开发。啮齿动物临床前研究的成功完成将使Radix Pharmaceuticals能够筹集更多资金，并吸引商业合作伙伴将候选药物推向市场。III期随访工作将包括恒河猴的临床前数据（PK、毒性和疗效）（FDA要求在相同实验室条件下生产的两个种属的数据），然后是GMP生产和GLP评价。研究性新药（IND）申请将提交给FDA。Radix Pharmaceuticals与商业合作伙伴建立了战略联盟，进行III期开发。

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. SBIR Phase I research and additional work at Radix Pharmaceuticals have demonstrated that some novel febrifugine analogues are potent inhibitors of both sensitive and multi-drug resistant human malaria strains in vitro at low nanomolar concentrations. These compounds possess new mode of action by impairing haemazoin formation required for maturation of the parasite at the trophozoite stage. Synthesized compounds demonstrated low toxicity in human adult liver epithelial cells and freshly isolated rat hepatocytes. No in vitro cardiotoxicity or genotoxicity was observed. A scalable synthetic route to make radioactive [3H] compounds for PK studies has been established. FDA suggestions have been obtained regarding the necessary ongoing pre-clinical studies to warrant investigational new drug (IND) submission. Based on successful completion of the feasibility study, the overall goal of this Phase II project is to establish detailed pre-clinical profiles for the candidates. Under Phase II support, we will perform the scale up synthesis of these compounds and begin pre-clinical studies in animal models to obtain toxicity, pharmacokinetics, and efficacy data. The following interactive studies will be performed to obtain rodent pre-clinical profiles efficiently and effectively: (i) The six compounds identified in Phase I research will be synthesized in a larger scale (2-3 kg per compound) for efficacy and toxicity studies as well as in radioactive [3H] form (100 mg per compound) for pharmacokinetic studies. (ii) Test compounds will be tested in rodent models to obtain acute and sub-acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. (iii) Test compounds will be administered intraperitoneally, subcutaneously, or orally to rats and mice and pharmacokinetic parameters will be calculated. (iv) 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. These pre-clinical studies would clearly validate the candidate's potential as an ideal new drug for the treatment of acute malaria. On completion of the Phase II studies, one or two compounds that are orally active and possess good bioavailability and therapeutic index will be selected for further development. 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 the market. Phase III follow up work would include pre-clinical data (PK, toxicity, and efficacy) in Rhesus monkey (having data from two species that were produced under the same laboratory conditions is required by FDA), followed by GMP manufacturing and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA. Radix Pharmaceuticals has strategic alliance with commercial partners for Phase III development.