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Quabodepistat (OPC-167832) is a novel carbostyril derivative developed by Otsuka with potent antituberculosis activity, acting as a DprE1 (decaprenylphosphoryl-β-d-ribose 2′-oxidase) Inhibitor. 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.
| Targets |
OPC-167832 targets DprE1 (decaprenyl phosphoryl-β-d-ribose 2′-oxidase) with an IC50 of 0.258 μM[1]
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| ln Vitro |
The MIC of quodepistat (OPC-167832) against lab strains is extremely low. MIC values for tuberculosis H37Rv (0.0005 μg/ml) and Kurono (0.0005 μg/ml) as well as for monoresistant strains of rifampicin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (STR), and pyrazinamide (PZA) range from 0.00024 to 0.001 μg/ml. Quabodepistat, however, exhibits negligible or no activity against common anaerobic and aerobic non-mycobacterial bacterial strains [1]. Quabodepistat has IC90 values of 0.0048 and 0.0027 μg/ml against intracellular Mycobacterium TB strains H37Rv and Kurono, respectively. At low doses, quabodepistat exhibits bactericidal action against intracellular Mycobacterium TB; at concentrations of 0.004 μg/ml or above, the bactericidal activity achieves saturation [1].
- Antimicrobial activity against Mycobacterium tuberculosis: The minimum inhibitory concentration (MIC) ofOPC-167832against laboratory strains (H37Rv and Kurono) and monoresistant strains (resistant to rifampicin, isoniazid, ethambutol, streptomycin, or pyrazinamide) ranged from 0.00024 to 0.002 μg/mL. It exhibited bactericidal activity against both replicating and intracellular bacilli. For intracellularM. tuberculosisH37Rv and Kurono, the IC90 values were 0.0048 μg/mL and 0.0027 μg/mL, respectively, and saturated bactericidal activity was observed at concentrations ≥0.004 μg/mL[1] - Spontaneous resistance frequency : The frequency of spontaneous resistance inM. tuberculosisH37Rv was less than 1.91 × 10⁻⁷[1] - Interaction with other anti-TB agents : No antagonistic effects were found whenOPC-167832was combined with other anti-tuberculosis drugs (such as rifampicin, isoniazid) in in vitro checkerboard assays[1] |
| ln Vivo |
Good pharmacokinetic characteristics are exhibited by quabodepistat (OPC-167832) (published article; 0.625-10 mg/kg). With a half-life (t1/2) of 1.3 to 2.1 hours, quabodepistat in the lungs has a dose-dependent Cmax and AUCt that peak at 0.5 to 1.0 hours (tmax)[1]. It also eliminates a 2-fold concentration of quabodepistat in the lungs. Comparing quabodepistat (interface; 0.625–10 mg/kg; 4 weeks) to vehicle resulted in a significant reduction in lung CFU. Lung CFU decreased from 0.625 mg/kg to 2.5 mg/kg in a dose-dependent manner. Infection with M. Kurono in the ICR female model. When Quabodepistat is taken orally in conjunction with DMD, BDQ, or LVX, it works best when taken in combination with other medications [1]. In comparison to DC and DCB, quobedepistat (gavage; 2.5 mg/kg; combined with DCMB; 12 weeks) demonstrated the most efficacious treatment. CFU counts in the lungs following 6 weeks of treatment were below the limit of detection, while by the completion of the standard 8 weeks of treatment, all evaluated bacteria had been eliminated from the lungs of all mice [1].
Efficacy in a mouse model of chronic tuberculosis : In mice infected withM. tuberculosisKurono, OPC-167832showed dose-dependent bactericidal activity when administered orally. A significant reduction in lung colony-forming units (CFU) was observed at 2.5 mg/kg, and near-complete eradication was achieved at 10 mg/kg after 4 weeks of treatment. Combination with delamanid, bedaquiline, or levofloxacin enhanced efficacy, with 3- or 4-drug regimens (e.g., delamanid +OPC-167832+ bedaquiline/moxifloxacin/linezolid) resulting in greater reduction of bacterial burden and better prevention of relapse compared to standard therapy[1] |
| Enzyme Assay |
Efficacy in a mouse model of chronic tuberculosis : In mice infected withM. tuberculosisKurono, OPC-167832showed dose-dependent bactericidal activity when administered orally. A significant reduction in lung colony-forming units (CFU) was observed at 2.5 mg/kg, and near-complete eradication was achieved at 10 mg/kg after 4 weeks of treatment. Combination with delamanid, bedaquiline, or levofloxacin enhanced efficacy, with 3- or 4-drug regimens (e.g., delamanid +OPC-167832+ bedaquiline/moxifloxacin/linezolid) resulting in greater reduction of bacterial burden and better prevention of relapse compared to standard therapy[1]
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| Cell Assay |
differentiated and infected withM. tuberculosisH37Rv or Kurono, then treated withOPC-167832at concentrations ranging from 0.001 to 0.01 μg/mL. After 72 hours of treatment, intracellular CFU were counted to evaluate the bactericidal effect, which showed a concentration-dependent pattern[1]
- Checkerboard assay for drug interaction : Microtiter plate-based broth dilution was used to test the interaction betweenOPC-167832and other anti-TB drugs. Fractional inhibitory concentration indices (FICI) were calculated to determine the nature of the interaction[1] |
| Animal Protocol |
Animal/Disease Models: ICR mouse[1]
Doses: 0.625-10 mg/kg Route of Administration: Oral; 0.625-10 mg/kg; 4 weeks Experimental Results: Demonstrated in vivo efficacy in mouse chronic tuberculosis model. - Mouse infection and treatment : Female ICR mice (6-8 weeks old) were infected intranasally withM. tuberculosisKurono. OPC-167832was administered orally at doses of 0.625-10 mg/kg daily for 4-12 weeks. Lung and spleen homogenates were cultured to enumerate CFU for efficacy evaluation. For combination studies, OPC-167832(2.5 mg/kg) was co-administered with delamanid (2.5 mg/kg), bedaquiline (10 mg/kg), or levofloxacin (50 mg/kg)[1] - Drug formulation : OPC-167832was dissolved in 0.5% methylcellulose or dimethyl sulfoxide (DMSO) for oral gavage administration[1] |
| ADME/Pharmacokinetics |
In mice, after oral administration ofOPC-167832at doses of 0.625-10 mg/kg, peak plasma concentrations (Cmax) were reached within 0.5-1.0 hours, and the area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24h) showed a dose-dependent increase. The terminal half-life (T1/2) ranged from 1.3 to 2.1 hours. Lung concentrations were approximately 2-fold higher than plasma concentrations, and levels remained above the MIC in caseous necrotic lesions[1]
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| Toxicity/Toxicokinetics |
In preclinical studies, no significant hepatic or renal toxicity was observed in rodents, and no mortality occurred at doses up to 100 mg/kg[1]
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| References |
[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.
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| Additional Infomation |
- Mechanism of action : OPC-167832inhibits DprE1, thereby blocking the biosynthesis of arabinogalactan, a critical component of the mycobacterial cell wall[1]
- Combination potential : OPC-167832shows synergistic effects with delamanid, bedaquiline, and fluoroquinolones, indicating its potential for use in shorter treatment regimens[1] |
| Molecular Formula |
C21H20CLF3N2O4
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|---|---|
| Molecular Weight |
456.8462
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| Exact Mass |
456.106
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| Elemental Analysis |
C, 55.21; H, 4.41; Cl, 7.76; F, 12.48; N, 6.13; O, 14.01
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| CAS # |
1883747-71-4
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| PubChem CID |
118904282
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| Appearance |
White to light yellow solid powder
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| Density |
1.485±0.06 g/cm3(Predicted)
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| Boiling Point |
645.6±55.0 °C(Predicted)
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
652
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| Defined Atom Stereocenter Count |
2
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| SMILES |
ClC1C=C(C(=C(C=1)F)N1CC[C@@](COC2C=CC(=C3C=2CCC(N3)=O)F)([C@@H](C1)O)O)F
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| InChi Key |
XZISSTDXPBUCJA-DYESRHJHSA-N
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| InChi Code |
InChI=1S/C21H20ClF3N2O4/c22-11-7-14(24)20(15(25)8-11)27-6-5-21(30,17(28)9-27)10-31-16-3-2-13(23)19-12(16)1-4-18(29)26-19/h2-3,7-8,17,28,30H,1,4-6,9-10H2,(H,26,29)/t17-,21-/m1/s1
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| Chemical Name |
5-(((3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl)methoxy)-8-fluoro-3,4-dihydroquinolin-2(1H)-one
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| Synonyms |
OPC 167832; OPC167832O; QUABODEPISTAT; OPC-167832; UNII-1PQN78P4S3; 1PQN78P4S3; QUABODEPISTAT [INN]; 5-[[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy]-8-fluoro-3,4-dihydro-1H-quinolin-2-one; 2(1H)-QUINOLINONE, 5-(((3R,4R)-1-(4-CHLORO-2,6-DIFLUOROPHENYL)-3,4-DIHYDROXY-4-PIPERIDINYL)METHOXY)-8-FLUORO-3,4-DIHYDRO-; ...; 1883747-71-4; OPC-167832
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~180 mg/mL (~394.01 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.5 mg/mL (9.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 45.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1889 mL | 10.9445 mL | 21.8890 mL | |
| 5 mM | 0.4378 mL | 2.1889 mL | 4.3778 mL | |
| 10 mM | 0.2189 mL | 1.0945 mL | 2.1889 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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