OPC-167832
(Synonyms: OPC-167832) 目录号 : GC63130
OPC-167832 是一种有效的口服活性 dprE1 抑制剂，其>IC50 为 0.258 μM。OPC-167832 具有抗结核活性，可用于由结核分枝杆菌引起的结核病的相关研究。
Cas No.:1883747-71-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
OPC-167832 is a potent and orally active dprE1 Inhibitor with an IC50 of 0.258 μM. OPC-167832 has antituberculosis activity and can be used for the research of tuberculosis caused by Mycobacterium tuberculosis[1].
OPC-167832 exhibits very low MICs against laboratory strains of M. tuberculosis H37Rv (MIC: 0.0005 μg/ml) and Kurono (MIC: 0.0005 μg/ml) and strains with monoresistance to rifampin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (STR), and pyrazinamide (PZA) (MIC: 0.00024-0.001 μg/ml). However, OPC-167832 has minimal or no activity against standard strains of nonmycobacterial aerobic and anaerobic bacteria[1].The IC90 values of OPC-167832 against intracellular M. tuberculosis strains H37Rv and Kurono are 0.0048 and 0.0027 μg/ml, respectively. OPC-167832 shows bactericidal activity against intracellular M. tuberculosis at a low concentration, and the bactericidal activity is saturated at concentrations of 0.004 μg/ml or higher[1].
OPC-167832 (oral administration; 0.625-10 mg/kg) exhibits a good pharmacokinetic characteristic. The plasma reaches peak at 0.5 h to 1.0 h (tmax) and is eliminated with a half-life (t1/2) of 1.3 h to 2.1 h OPC-167832 distribution in the lungs is approximately 2 times higher than that in plasma, and the Cmax and AUCt of OPC-167832 in plasma and the lungs shows dose dependency[1].OPC-167832 (oral administration; 0.625-10 mg/kg; 4 weeks) significantly reduces lung CFU compared to the vehicle group. The dose-dependent decrease of lung CFU is observed from 0.625 mg/kg to 2.5 mg/kg. In a M. tuberculosis Kurono-infected ICR female mice model. OPC-167832 combines with DMD, BDQ, or LVX via oral gavage exhibits significantly higher efficacies than each single agent alone[1].[1].OPC-167832 (oral gavage; 2.5 mg/kg; combination with DCMB; 12 weeks) demonstrates the most potent efficacy when compares with DC, DCB. The lung CFU count after 6 weeks of treatment is below the detection limit, and at the end of just 8 weeks of treatment, the bacteria in the lungs of all the evaluated mice had already been eradicate[1].
[1]. Norimitsu Hariguchi, et al. OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor.Antimicrob Agents Chemother. 2020 May 21;64(6):e02020-19.
| Cas No. | 1883747-71-4 | SDF | |
| 别名 | OPC-167832 | ||
| 分子式 | C21H20ClF3N2O4 | 分子量 | 456.84 |
| 溶解度 | DMSO : 180 mg/mL (394.01 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 | 2.189 mL | 10.9448 mL | 21.8895 mL |
| 5 mM | 0.4378 mL | 2.189 mL | 4.3779 mL |
| 10 mM | 0.2189 mL | 1.0945 mL | 2.189 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。
OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor
Antimicrob Agents Chemother 2020 May 21;64(6):e02020-19.PMID:32229496DOI:10.1128/AAC.02020-19.
There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1.91 × 10-7 It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole-genome and targeted sequencing of isolates resistant to OPC-167832 identified decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of the compound, and further studies demonstrated inhibition of DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg of body weight. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3- or 4-drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed efficacy in reducing the bacterial burden and preventing relapse superior to that of the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.
Mycobacterium tuberculosis DprE1 Inhibitor OPC-167832 Is Active against Mycobacterium abscessus In Vitro
Antimicrob Agents Chemother 2022 Dec 20;66(12):e0123722.PMID:36350151DOI:10.1128/aac.01237-22.
The antituberculosis candidate OPC-167832, an inhibitor of DprE1, was active against Mycobacterium abscessus. Resistance mapped to M. abscessus dprE1, suggesting target retention. OPC-167832 was bactericidal and did not antagonize activity of clinical anti-M. abscessus antibiotics. Due to its moderate potency compared to that against Mycobacterium tuberculosis, the compound lacked efficacy in a mouse model and is thus not a repurposing candidate. These results identify OPC-167832-DprE1 as a lead-target couple for a M. abscessus-specific optimization program.
Development of a Practical Synthesis of the 8-FDC Fragment of OPC-167832
ACS Omega 2022 Feb 18;7(8):7223-7228.PMID:35252712DOI:10.1021/acsomega.1c06996.
A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril (8-FDC) fragment of OPC-167832 in 41% yield and in >99% purity over four steps from 3-amino-4-fluorophenol. The key feature of this process is the development of a telescoped one-pot synthesis of the quinolone via a chemoselective amidation/acid-induced cyclization that allows for simple product isolation without the need for column chromatography.
Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models
Antimicrob Agents Chemother 2022 Apr 19;66(4):e0239821.PMID:35315690DOI:10.1128/aac.02398-21.
A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.
Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 Inhibitors TBA-7371, PBTZ169, and OPC-167832
Antimicrob Agents Chemother 2021 Oct 18;65(11):e0058321.PMID:34370580DOI:10.1128/AAC.00583-21.
Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.