Figure 1.
Chemical structures of compounds.
Table 1.
In vitro activity of SCYX-7158.
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.
Table 2.
Activity of SCYX-7158 in T. b. brucei acute mouse infections.
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.
Table 3.
In vitro physicochemical and ADME properties of SCYX-7158.
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.