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Acoziborole (SCYX-7158) Sale

(Synonyms: 4-氟-N-(1-羟基-3,3-二甲基-1,3-二氢苯并[C][1,2]噁硼戊环-6-基)-2-(三氟甲基)苯甲酰胺,SCYX-7158; AN5568) 目录号 : GC32137

Acoziborole (SCYX-7158) (SCYX-7158) 是一种有效、安全和具有口服活性的抗原虫剂,用于人类非洲锥虫病 (HAT) 的研究。

Acoziborole (SCYX-7158) Chemical Structure

Cas No.:1266084-51-8

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥3,465.00
现货
1mg
¥1,431.00
现货
5mg
¥3,150.00
现货
10mg
¥5,220.00
现货

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Sample solution is provided at 25 µL, 10mM.

Description

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.

实验参考方法

Cell experiment:

Compounds (e.g., Acoziborole) to be tested are serially diluted in DMSO and added to 96-well plates to give final concentrations ranging from 5 to 0.01 µg/mL. T. b. brucei parasites in the log phase of growth are diluted in HMI-9 media and added to each well for a final concentration of 1×104 parasites per well. For the sensitivity assays using T. b. rhodesiense and T. b. gambiense, pararasites are cultured in MEM supplemented with Baltz components, diluted in the aforementioned culture media, and added to each well at a density of 1×103 cells/well. The final concentration of DMSO is 0.5% and the total volume is 100 µL/well. After 72 h incubation, Resazurin is added to each well (20 µL of 25 mg/100 mL stock in PBS) and incubated for an additional 4-6 h. To assess cell viability, fluorescence is quantified using an EnVision Multilabel Plate Reader at an excitation wavelength of 530 nm and emission of 590 nm. Triplicate data points are averaged to generate sigmoidal dose-response curves and determine IC50 values using XLfit curve fitting software. The IC50 is defined as the amount of compound required to decrease parasite or cell viability by 50% compared to those grown in the absence of the test compound. The MIC, defined as the lowest concentration of compound that completely inhibits visible parasite growth, is determined by visual inspection of 96-well plates after 48-72 h of incubation with the test compounds. To evaluate the effects of serum on trypanocidal activity, assays are performed in the presence of increasing concentration (2.5% to 50%) of fetal calf serum. The results are expressed as a fold-change in IC50 values relative to standard conditions (10% FCS) [1].

Animal experiment:

Mice, Rats and Monkeys[1]Male CD-1 mice (~25 g), male Sprague-Dawley rats (~225 g), or male cynomolgus monkeys (~3-5 kg) are administered test article by either bolus intravenous injection (IV) or oral gavage. Male CD-1 mice, Sprague-Dawley rats, cynomolgus monkeys or male beagle dogs are administered a single oral dose of Acoziborole at a dose of 25 mg/kg (mouse, rat) or 10 mg/kg (monkey, dog). Blood samples are collected and analyzed.

References:

[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.

化学性质

Cas No. 1266084-51-8 SDF
别名 4-氟-N-(1-羟基-3,3-二甲基-1,3-二氢苯并[C][1,2]噁硼戊环-6-基)-2-(三氟甲基)苯甲酰胺,SCYX-7158; AN5568
Canonical SMILES O=C(NC1=CC=C2C(C)(C)OB(O)C2=C1)C3=CC=C(F)C=C3C(F)(F)F
分子式 C17H14BF4NO3 分子量 367.1
溶解度 DMSO : ≥ 125 mg/mL (340.51 mM) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.7241 mL 13.6203 mL 27.2405 mL
5 mM 0.5448 mL 2.7241 mL 5.4481 mL
10 mM 0.2724 mL 1.362 mL 2.7241 mL
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