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

Nare, B. and Wring, S. and Bacchi, C. and Beaudet, B. and Bowling, T. and Brun, R. and Chen, D. and Ding, C. and Freund, Y. and Gaukel, E. and Hussain, A. and Jarnagin, K. and Jenks, M. and Kaiser, M. and Mercer, L. and Mejia, E. and Noe, A. and Orr, M. and Parham, R. and Plattner, J. and Randolph, R. and Rattendi, D. and Rewerts, C. and Sligar, J. and Yarlett, N. and Don, R. and Jacobs, R.. (2010) Discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late stage central nervous system African Trypanosomiasis. Antimicrobial agents and chemotherapy : AAC, Vol. 54, H. 10. pp. 4379-4388.

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Official URL: http://edoc.unibas.ch/dok/A5842871

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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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 07:18
Deposited On:14 Sep 2012 06:46

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