ACX-362E
(Synonyms: ACX-362E; GLS-362E) 目录号 : GC35247
ACX-362E (ACX-362E) 是一流的、具有口服活性的 DNA 聚合酶 IIIC (pol IIIC) 抑制剂，Ki 为 0.325 μM 用于来自 C 的 DNA pol IIIC。
Cas No.:1275582-97-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ACX-362E is an orally available DNA polymerase IIIC (pol IIIC) inhibitor, acts as an antimicrobial agent to treat Gram-positive infections, with a MIC50 of 2 μg/mL for C. difficile. ACX-362E displays very potent in vitro and in vivo activities against broad spectrum of C. difficile pathogens[1]. MIC50: 2 μg/mL (C. difficile)[1]
[1]. Xu WC, et al. Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections. Bioorg Med Chem. 2019 Jun 11. pii: S0968-0896(19)30663-7.
| Cas No. | 1275582-97-2 | SDF | |
| 别名 | ACX-362E; GLS-362E | ||
| Canonical SMILES | O=C1NC(NCC2=CC=C(Cl)C(Cl)=C2)=NC3=C1N(CCN4CCOCC4)C=N3 | ||
| 分子式 | C18H20Cl2N6O2 | 分子量 | 423.3 |
| 溶解度 | DMSO : 62.5 mg/mL (147.65 mM; Need ultrasonic) | 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3624 mL | 11.812 mL | 23.6239 mL |
| 5 mM | 0.4725 mL | 2.3624 mL | 4.7248 mL |
| 10 mM | 0.2362 mL | 1.1812 mL | 2.3624 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。
In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile
J Antimicrob Chemother 2020 Aug 1;75(8):2149-2155.PMID:32285102DOI:10.1093/jac/dkaa134.
Background: Ibezapolstat (ACX-362E) is the first DNA polymerase IIIC inhibitor undergoing clinical development for the oral treatment of Clostridioides difficile infection (CDI). Methods: In this study, the in vitro activity of ibezapolstat was evaluated against a panel of 104 isolates of C. difficile, including those with characterized ribotypes (e.g. 027 and 078) and those producing toxin A or B and was shown to have similar activity to those of comparators against these strains. Results: The overall MIC50/90 (mg/L) for ibezapolstat against evaluated C. difficile was 2/4, compared with 0.5/4 for metronidazole, 1/4 for vancomycin and 0.5/2 for fidaxomicin. In addition, the bactericidal activity of ibezapolstat was evaluated against actively growing C. difficile by determining the MBC against three C. difficile isolates. Time-kill kinetic assays were additionally performed against the three C. difficile isolates, with metronidazole and vancomycin as comparators. Conclusions: The killing of C. difficile by ibezapolstat was observed to occur at concentrations similar to its MIC, as demonstrated by MBC:MIC ratios and reflected in time-kill kinetic assays. This activity highlights the therapeutic potential of ibezapolstat for the treatment of CDI.
Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections
Bioorg Med Chem 2019 Aug 1;27(15):3209-3217.PMID:31221610DOI:10.1016/j.bmc.2019.06.017.
Despite the growing global crisis caused by antimicrobial drug resistance among pathogenic bacteria, the number of new antibiotics, especially new chemical class of antibiotics under development is insufficient to tackle the problem. Our review focuses on an emerging class of antibacterial therapeutic agents that holds a completely novel mechanism of action, namely, inhibition of bacterial DNA polymerase IIIC. The recent entry of this new class into human trials may herald the introduction of novel drugs whose novel molecular target precludes cross-resistance with existing antibiotic classes. This review therefore examines the evolution of DNA pol IIIC inhibitors from the discovery of 6-(p-hydroxyphenylazo)uracil (HPUra) in the 1960s to the development of current first-in-class N7-substituted guanine drug candidate ACX-362E, now under clinical development for the treatment of Clostridioides difficile infection.
Investigational Treatment Agents for Recurrent Clostridioides difficile Infection (rCDI)
J Exp Pharmacol 2020 Oct 9;12:371-384.PMID:33116952DOI:10.2147/JEP.S242959.
Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea that is deemed a global health threat. C. difficile strain BI/NAP1/027 has contributed to the increase in the mortality, severity of CDI outbreaks and recurrence rates (rCDI). Updated CDI treatment guidelines suggest vancomycin and fidaxomicin as initial first-line therapies that have initial clinical cure rates of over 80%. Unacceptably high recurrence rates of 15-30% in patients for the first episode and 40% for the second recurrent episode are reported. Alternative treatments for rCDI include fecal microbiota transplant and a human monoclonal antibody, bezlotoxumab, that can be used in patients with high risk of rCDI. Various emerging potential therapies with narrow spectrum of activity and little systemic absorption that are in development include 1) Ibezapolstat (formerly ACX-362E), MGB-BP-3, and DS-2969b-targeting bacterial DNA replication, 2) CRS3213 (REP3123)-inhibiting toxin production and spore formation, 3) ramizol and ramoplanin-affecting bacterial cell wall, 4) LFF-571-blocking protein synthesis, 5) Alanyl-L-Glutamine (alanylglutamine)-inhibiting damage caused by C. difficile by protecting intestinal mucosa, and 6) DNV3837 (MCB3681)-prodrug consisting of an oxazolidinone-quinolone combination that converts to the active form DNV3681 that has activity in vitro against C. difficile. This review article provides an overview of these developing drugs that can have potential role in the treatment of rCDI and in lowering recurrence rates.
Investigational drug therapies currently in early-stage clinical development for the treatment of clostridioides (clostridium) difficile infection
Expert Opin Investig Drugs 2019 Apr;28(4):323-335.PMID:30753786DOI:10.1080/13543784.2019.1581763.
Introduction: Clostridioides (Clostridium) difficile Infection (CDI) is an urgent global threat causing ~500,000 infections annually in the United States of America (USA) and is associated with a 36% 30-day attributable mortality rate. Despite the availability of three therapeutic agents, CDI recurrence occurs in 20-40% of patients, with a 30-40% second recurrence rate in these patients. Consequently, there is a need for novel agents for treating CDI. Areas covered: We searched MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for agents in early stages of clinical development. These drugs include ACX-362E, DS-2969b, LFF 571, RBX2660, ribaxamase, ridinilazole that have advanced to at least phase 2 and several other drugs in phase 1 development. Expert opinion: The challenge for these new agents is three-fold: (1) to have a novel approach such as a different target/mechanism of action; (2) be 'significantly' better than existing agents in regard to 'sustained clinical response'; or (3) be priced at a reasonable cost when it comes to market or perhaps all three. Their utility can only be proven by clinical trials.
Genome Location Dictates the Transcriptional Response to PolC Inhibition in Clostridium difficile
Antimicrob Agents Chemother 2019 Jan 29;63(2):e01363-18.PMID:30455241DOI:10.1128/AAC.01363-18.
Clostridium difficile is a potentially lethal gut pathogen that causes nosocomial and community-acquired infections. Limited treatment options and reports of reduced susceptibility to current treatment emphasize the necessity for novel antimicrobials. The DNA polymerase of Gram-positive organisms is an attractive target for the development of antimicrobials. ACX-362E [N2-(3,4-dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine; MorE-DCBG] is a DNA polymerase inhibitor in preclinical development as a novel therapeutic against C. difficile infection. This synthetic purine shows preferential activity against C. difficile PolC over those of other organisms in vitro and is effective in an animal model of C. difficile infection. In this study, we have determined its efficacy against a large collection of clinical isolates. At concentrations below the MIC, the presumed slowing (or stalling) of replication forks due to ACX-362E leads to a growth defect. We have determined the transcriptional response of C. difficile to replication inhibition and observed an overrepresentation of upregulated genes near the origin of replication in the presence of PolC inhibitors, but not when cells were subjected to subinhibitory concentrations of other antibiotics. This phenomenon can be explained by a gene dosage shift, as we observed a concomitant increase in the ratio between origin-proximal and terminus-proximal gene copy number upon exposure to PolC inhibitors. Moreover, we show that certain genes differentially regulated under PolC inhibition are controlled by the origin-proximal general stress response regulator sigma factor B. Together, these data suggest that genome location both directly and indirectly determines the transcriptional response to replication inhibition in C. difficile.