SCYX-7158可安全按有效地用于治疗人类非洲锥虫病(HAT)。作用于T.b.bruceiS427菌株，MIC值为0.6μg/mL。
CAS：1266084-51-8
分子式：C17H14BF4NO3
分子量：367.1
纯度：98%
存储：Store at -20°C

Background:

SCYX-7158 is an effective, safe and orally active treatment for human african trypanosomiasis (HAT). In the T. b. brucei S427 strain, the MIC value for SCYX-7158 is 0.6 µg/mL.

SCYX-7158 is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense.In whole cell assays, SCYX-7158 exhibits potent activity against representative T. b. brucei, T. b. rhodesiense and T. b. gambiense strains. IC50 values for SCYX-7158 are approximately 0.07 µg/mL to 0.37 µg/mL following incubation of the parasite strains with SCYX-7158 for 72 h. In the T. b. brucei S427 strain, the MIC value for SCYX-7158 is 0.6 µg/mL, approximately two times the IC50 measured for this strain. In contrast to the potent activity of SCYX-7158 against trypanosomes, no significant inhibition of cell proliferation is observed in an in vitro mammalian cell (L929 mouse cell line) assay at drug concentrations up to 50 µg/mL. The potential for SCYX-7158 to inhibit cytochrome P450 (CYP) enzymes is evaluated using P450-Glo assays for the human isoforms CYP3A4, CYP1A2, CYP2C19, CYP2C9 and CYP2D6. The IC50 values for SCYX-7158 in these assays are all above 10 µM[1].

In uninfected mice, 4.3 mg/kg intravenous dose of SCYX-7158 show an apparent elimination half-life (t1/2) of 26.6 h; systemic clearance (CL) of 0.089 L/h/kg; a volume of distribution (Vdss) of 1.69 L/kg and area under the concentration-time curve (AUC0-24 h) of 48 h•μg/mL. Following an oral dose of 13.4 mg/kg, which corresponds to the lowest efficacious dose in the murine stage 2 HAT model, SCYX-7158 is rapidly absorbed, as a Cmax of 6.96 µg/mL is achieved in plasma at 6 h after dose, with an oral clearance (Cl/F) value of 0.163 L/h/kg, an AUC0-24 h of 82 h•μg/mL and absolute oral bioavailability of 55%. After a 26 mg/kg oral dose, which corresponds to the dose giving a 100% cure rate in the murine stage 2 HAT model, Cmax increases to 9.8 µg/mL and the AUC0-24 h is 113 h•μg/mL. In uninfected rats, following oral administration of SCYX-7158 at a nominal dose of 25 mg/kg (dose affording a 100% cure rate in mice), Cmax increases approximately 2 fold more than that in mice (Cmax=18.2 µg/mL) and AUC0-24 h, and hence oral clearance, improves approximately 4 fold (AUC0-24 h 291 h•μg/mL and CL/F=0.092 L/kg/h). The time to maximum concentration is similar to that in mice (tmax=8 h). Uninfected male and female cynomolgus monkeys are treated with SCYX-7158 at 2 mg/kg (IV) on study day 1 and 10 mg/kg (NG) on study day 8. SCYX-7158 exhibits excellent plasma pharmacokinetics, with CL of 0.022 L/h/kg; Vdss of 0.656 L/kg and area under the concentration-time curve 78.8 h•μg/mL, and 94.4 for AUC0-24 h and AUC0-inf, respectively, following intravenous administration[1].

[1]. Jacobs RT, et al. SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Negl Trop Dis. 2011 Jun;5(6):e1151.