SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

SCYX-7158 exhibits excellent plasma exposure across species.

<p>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 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001151#s2" target="_blank">Methods</a> 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.</p

Time vs. concentration curves for SCYX-7158 following administration to mice infected with <i>T. b. brucei</i> TREU667.

<p>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 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001151#s2" target="_blank">Methods</a> 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.</p

<i>In vitro</i> trypanocidal activity of SCYX-7158.

<p><b>a</b>, Parasite viability, as indicated by ATP content, following continuous exposure of <i>T. b. brucei</i> 427 to SCYX-7158 at the indicated concentrations and times. Data are mean ± s.d. <b>b</b>, Irreversibility of trypanocidal effect. <i>T. b. brucei</i> 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 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001151#s2" target="_blank">Methods</a> section.</p

Chemical structures of compounds.

<p>Chemical structures of compounds.</p

<i>In vitro</i> activity of SCYX-7158.

<p><i>In vitro</i> activity of SCYX-7158.</p

Activity of SCYX-7158 in <i>T. b. brucei</i> acute mouse infections.

<p>Activity of SCYX-7158 in <i>T. b. brucei</i> acute mouse infections.</p

<i>In vitro</i> physicochemical and ADME properties of SCYX-7158.

<p><i>In vitro</i> physicochemical and ADME properties of SCYX-7158.</p