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In stage 2 disease (central nervous system [CNS] involvement), mice infected with<jats:italic>T. b. brucei<\/jats:italic>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 subchronic toxicity. Metabolism and pharmacokinetic studies in several species, including nonhuman 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 the ability to cross the blood-brain barrier with no evidence of interaction with the 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<jats:italic>T. brucei<\/jats:italic>subspecies, excellent physicochemical profiles,<jats:italic>in vitro<\/jats:italic>metabolic stability, a low potential for CYP450 inhibition, a 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 the development of new and effective orally administered treatments for human African trypanosomiasis.<\/jats:p>","DOI":"10.1128\/aac.00498-10","type":"journal-article","created":{"date-parts":[[2010,7,27]],"date-time":"2010-07-27T00:51:41Z","timestamp":1280191901000},"page":"4379-4388","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":94,"title":["Discovery of Novel Orally Bioavailable Oxaborole 6-Carboxamides That Demonstrate Cure in a Murine Model of Late-Stage Central Nervous System African Trypanosomiasis"],"prefix":"10.1128","volume":"54","author":[{"given":"Bakela","family":"Nare","sequence":"first","affiliation":[{"name":"Scynexis, Inc., Research Triangle Park, North 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