Pre-Clinical Development of Natural Product Analogues as Antimalarial Agents

描述(申请人提供)：该项目的长期目标是开发一种廉价、口服有效、无毒并能治愈恶性疟疾的新药(新化学实体[NCE])。SBIR第一阶段研究和Radix制药公司的其他工作已经证明，一些新的febrifugine类似物在体外低纳摩尔浓度下对敏感和多药耐药的人类疟疾菌株都是有效的抑制剂。这些化合物具有新的作用方式，通过损害滋养体阶段寄生虫成熟所需的血偶氮素形成。合成的化合物对成人肝上皮细胞和新鲜分离的大鼠肝细胞均表现出较低的毒性。未观察到体外心脏毒性和遗传毒性。已经建立了一条可扩展的合成路线，以制造用于PK研究的放射性[~3H]化合物。FDA已经获得了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)的提交。在成功完成可行性研究的基础上，这一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。在第二阶段的支持下，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。将进行以下互动研究，以高效和有效地获得啮齿动物临床前概况：(I)第一阶段研究中确定的六种化合物将以更大规模(每种化合物2-3公斤)合成，用于疗效和毒性研究，以及以放射性[~3H]形式(每种化合物100毫克)合成，用于药代动力学研究。(Ii)测试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。(3)测试化合物将在大鼠和小鼠的腹膜内、皮下或口服给药，并计算药代动力学参数。(Iv)将获得感染人类疟疾品系的免疫受损的BXN小鼠和感染啮齿动物疟疾品系P.berghei的瑞士雄性白化小鼠的抗疟疾疗效数据。这些临床前研究将清楚地验证该候选药物作为治疗急性疟疾的理想新药的潜力。在第二阶段研究完成后，将选择一到两种具有口服活性、具有良好的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市场。第三阶段的后续工作将包括恒河猴的临床前数据(PK、毒性和疗效)(FDA要求拥有在相同实验室条件下生产的两个物种的数据)，随后将进行GMP制造和GLP评估。随后将向FDA提交研究用新药(IND)申请。Radix制药公司与商业伙伴建立了战略联盟，进行第三阶段的开发。

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.