Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late stage central nervous system African Trypanosomiasis

We report the discovery of novel boron-containing molecules, exemplified by N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-2-trifluoromethylbenzam ide (AN3520) and 4-Fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluorome thylbenzamide (SCYX-6759), as potent compounds against Trypanosoma brucei in vitro, including the two species responsible for human disease T. b. rhodesiense and T. b. gambiense. These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to10 mg/kg for 4 consecutive days. In stage 2 disease (central nervous system (CNS) involvement), mice infected with Trypanosoma brucei brucei (T. b. brucei) were cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole treated animals did not exhibit gross signs of compound-related acute or sub-chronic toxicity. Metabolism and pharmacokinetic studies in several species, including non-human primates, demonstrate that both SCYX-6759 and AN3520 are low clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated ability to cross the blood-brain barrier with no evidence of interaction with P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against all T. brucei subspecies, excellent physicochemical profiles, in vitro metabolic stability, low potential for CYP450 inhibition, lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for development of new and effective orally administered treatments for human African trypanosomiasis