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. ? ? ?
| Zhu, Shuren; Zhang, Quan; Gudise, Chandrashekar et al. (2007) Synthesis and evaluation of naphthyridine compounds as antimalarial agents. Bioorg Med Chem Lett 17:6101-6 |
