Acoziborole (SCYX-7158)
(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。
Cas No.:1266084-51-8
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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. | |
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.
| 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 |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Clinical and veterinary trypanocidal benzoxaboroles target CPSF3
Proc Natl Acad Sci U S A 2018 Sep 18;115(38):9616-9621.PMID:30185555DOI:10.1073/pnas.1807915115.
African trypanosomes cause lethal and neglected tropical diseases, known as sleeping sickness in humans and nagana in animals. Current therapies are limited, but fortunately, promising therapies are in advanced clinical and veterinary development, including Acoziborole (AN5568 or SCYX-7158) and AN11736, respectively. These benzoxaboroles will likely be key to the World Health Organization's target of disease control by 2030. Their mode of action was previously unknown. We have developed a high-coverage overexpression library and use it here to explore drug mode of action in Trypanosoma brucei Initially, an inhibitor with a known target was used to select for drug resistance and to test massive parallel library screening and genome-wide mapping; this effectively identified the known target and validated the approach. Subsequently, the overexpression screening approach was used to identify the target of the benzoxaboroles, Cleavage and Polyadenylation Specificity Factor 3 (CPSF3, Tb927.4.1340). We validated the CPSF3 endonuclease as the target, using independent overexpression strains. Knockdown provided genetic validation of CPSF3 as essential, and GFP tagging confirmed the expected nuclear localization. Molecular docking and CRISPR-Cas9-based editing demonstrated how Acoziborole can specifically block the active site and mRNA processing by parasite, but not host CPSF3. Thus, our findings provide both genetic and chemical validation for CPSF3 as an important drug target in trypanosomes and reveal inhibition of mRNA maturation as the mode of action of the trypanocidal benzoxaboroles. Understanding the mechanism of action of benzoxaborole-based therapies can assist development of improved therapies, as well as the prediction and monitoring of resistance, if or when it arises.
Optimal kinetic exposures for classic and candidate antitrypanosomals
J Antimicrob Chemother 2019 Aug 1;74(8):2303-2310.PMID:31093674DOI:10.1093/jac/dkz160.
Objectives: Efficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomals in vitro. Methods: An in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug. Results: Changing the shape of drug exposure significantly impacted drug efficacy. Suramin, melarsoprol and pentamidine were concentration-driven and therefore more efficacious when applied as short-lived high peaks. In contrast, difluoromethylornithine (DFMO) was time-driven, and therefore maximally effective as a constant infusion. Kinetic preference was robust over a wide range of drug exposures. Promising clinical candidates SCYX-7158 (Acoziborole) and fexinidazole (parent and sulfone) were concentration-driven, suggesting optimal clinical regimens would involve relatively high but intermittent dosing. Conclusions: Antitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.
Hypothesis-generating proteome perturbation to identify NEU-4438 and Acoziborole modes of action in the African Trypanosome
iScience 2022 Oct 7;25(11):105302.PMID:36304107DOI:10.1016/j.isci.2022.105302.
NEU-4438 is a lead for the development of drugs against Trypanosoma brucei, which causes human African trypanosomiasis. Optimized with phenotypic screening, targets of NEU-4438 are unknown. Herein, we present a cell perturbome workflow that compares NEU-4438's molecular modes of action to those of SCYX-7158 (Acoziborole). Following a 6 h perturbation of trypanosomes, NEU-4438 and Acoziborole reduced steady-state amounts of 68 and 92 unique proteins, respectively. After analysis of proteomes, hypotheses formulated for modes of action were tested: Acoziborole and NEU-4438 have different modes of action. Whereas NEU-4438 prevented DNA biosynthesis and basal body maturation, Acoziborole destabilized CPSF3 and other proteins, inhibited polypeptide translation, and reduced endocytosis of haptoglobin-hemoglobin. These data point to CPSF3-independent modes of action for Acoziborole. In case of polypharmacology, the cell-perturbome workflow elucidates modes of action because it is target-agnostic. Finally, the workflow can be used in any cell that is amenable to proteomic and molecular biology experiments.