SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis

Abstract

Background: Human 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 findings: A 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 C(max) >10 µg/mL and AUC(0-24 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/significance: The 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.

Figure 1. Chemical structures of compounds.

Figure 2. In vitro trypanocidal activity of SCYX-7158.

a, Parasite viability, as indicated by ATP content, following continuous exposure of T. b. brucei 427 to SCYX-7158 at the indicated concentrations and times. Data are mean ± s.d. b, Irreversibility of trypanocidal effect. T. b. brucei 427 were exposed to the indicated concentrations of SCYX-7158 for the time indicated, then were sedimented by centrifugation and resuspended in drug-free media. Parasite viability was measured at 72 h by the resazurin method as described in the Methods section.

Figure 3. SCYX-7158 cures stage 2 trypanosomiasis in mice.

Kaplan-Meier parasitemia plot for female Swiss-Webster mice (n = 10 per group) after infection with T. b. brucei TREU 667 (inoculum 1×10⁴ parasites). Oral treatment with SCYX-7158 started on day 21 after infection at the indicated doses (once daily for 7 days). Berenil (diminazene) was administered as a single 10 mg/kg dose intraperitoneally on either day 4 (positive control) or day 21 (negative control). Parasitemia was assessed weekly starting on day 21 by microscopic examination of a blood sample. Animals in which parasites were detected in the blood were sacrificed.

Figure 4. SCYX-7158 exhibits excellent plasma exposure across species.

Male CD-1 mice, Sprague-Dawley rats, cynomolgus monkeys or male beagle dogs were administered a single oral dose of SCYX-7158 at a dose of 25 mg/kg (mouse, rat) or 10 mg/kg (monkey, dog). Blood samples were collected and analyzed as described in the Methods section. Data points for mouse and rat represent a single animal at each time point; data points for cynomolgus monkey and dog represent the mean of three animals at each time point. The MIC line (red hashed line) is defined as the lowest concentration of compound that completely inhibits visible parasite growth, determined by visual inspection of 96-well test plates after 72 h incubation.

Figure 5. Time vs. concentration curves for SCYX-7158 following administration to mice infected with T. b. brucei TREU667.

Female Swiss Webster mice were administered 7 daily doses of SCYX-7158 at the indicated doses. Blood (solid lines) and brain (dashed lines) samples were collected after the last dose and analyzed as described in the Methods section. Data points represent a single mouse at each time point. The MIC line (red hashed line) is defined as the lowest concentration of compound that completely inhibits visible parasite growth, determined by visual inspection of 96-well test plates after 72 h incubation.