BackgroundHuman African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT.Methodology/Principal FindingsA drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with Cmax >10 µg/mL and AUC0–24 hr >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment.Conclusions/SignificanceThe biological and pharmacokinetic properties of SCYX-7158 suggest that this compound will be efficacious and safe to treat stage 2 HAT. SCYX-7158 has been selected to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011.

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(32), and treatment failures of up to 25% have been reported (12, 13). Difluoromethylornithine (DFMO) (Ornidyl) requires a 2-week therapy regimen which is difficult to administer in rural clinics (34). A new combination therapy with DFMO and oral nifurtimox (NECT) reduces the dose time to 1 week but still requires intravenous (i.v.) dosing (35).Antigenic variation is frequent, rendering prospects for vaccine development impracticable (22,27). What is urgently needed is a safe, orally (p.o.) administered drug, effective against both stages 1 and 2 of HAT, which then eliminates the need for staging and raises the potential for the eradication of sleeping sickness. Toward this aspiration, we have identified a class of boron-containing compounds, oxaborole carboxamides, as novel leads that show potent and selective trypanocidal activity in vitro. Two examples chosen from this lead series are AN3520 and SCYX-6759. These compounds exhibit rapid,