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VXc-486 (SPR-719) is a novel and potent gyrase B inhibitor with high bactericidal activity and the potential for treatment of tuberculosis and nontuberculosis mycobacterial infections. VXc-486 potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis, with MICs of 0.03 to 0.30 μg/ml and 0.08 to 5.48 μg/ml, respectively.
| Targets |
SPR719 (VXc-486) is a novel aminobenzimidazole inhibitor targeting the ATPase subunit GyrB (DNA gyrase B) of Mycobacterium tuberculosis. In a cell-free enzymatic assay using purified M. tuberculosis gyrase B, it showed an IC50 of <0.16 µg/mL and a Ki of <0.39 µg/mL. [1]
The compound also inhibits the homologous GyrB/ParE subunits in other bacteria, but shows negligible activity against human topoisomerase IIα. [1] |
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| ln Vitro |
SPR719 (VXc-486) exhibits potent antimycobacterial activity against a wide range of drug-sensitive (DS) and drug-resistant (DR) M. tuberculosis isolates, with MICs ranging from 0.03 to 0.30 µg/mL for DS isolates and 0.08 to 5.48 µg/mL for DR isolates. [1]
It is bactericidal against M. tuberculosis Erdman strain, achieving ≥3 log reduction in CFU after 14 days at 4× MIC (0.24 µg/mL). [1] The compound is active against non-replicating (dormant) M. tuberculosis in a low-oxygen recovery assay (LORA), with an IC50 of 0.26 µg/mL against H37Rv, which is more potent than moxifloxacin (IC50 1.60 µg/mL) and gatifloxacin (IC50 8.81 µg/mL). [1] It inhibits intracellular M. tuberculosis growth in THP-1 macrophages with an IC90 of 0.3 µg/mL. [1] SPR719 (VXc-486) also shows activity against nontuberculous mycobacteria (NTM), including M. abscessus (MIC50 1.0 µg/mL, MIC90 4.0 µg/mL), M. kansasii (MIC50 0.06 µg/mL, MIC90 0.5 µg/mL), M. avium (MIC 0.12–0.23 µg/mL), and Nocardia spp. (MIC 0.1–1.0 µg/mL). [1] |
| ln Vivo |
In a chronic tuberculosis mouse model (infected with M. tuberculosis Erdman), oral administration of SPR719 (VXc-486) (100 mg/kg twice daily) or its phosphate prodrug pVXc-486 (100 mg/kg twice daily) for 4 weeks significantly reduced lung bacterial burdens compared to early and late control groups. [1]
pVXc-486 showed superior in vivo efficacy compared to the parent compound, likely due to improved lung exposure. [1] When combined with rifapentine-pyrazinamide or bedaquiline-pyrazinamide in a relapse model, pVXc-486 sterilized M. tuberculosis infection in mice. [1] In a latent TB infection model, pVXc-486 monotherapy (100 mg/kg) showed activity comparable to isoniazid and approached that of rifampin. [1] |
| Enzyme Assay |
The enzymatic activity of M. tuberculosis gyrase B was assessed using a reconstituted heterotetrameric A₂B₂ complex. [1]
The assay couples ATP hydrolysis to the conversion of NADH to NAD⁺, monitored by absorbance decrease at 340 nm over 20 minutes using a microtiter plate reader. [1] The IC50 and Ki values for SPR719 (VXc-486) were determined from this assay. [1] |
| Cell Assay |
For intracellular activity, THP-1 macrophages were infected with luciferase-expressing M. tuberculosis H37Ra at an MOI of 2:1. [1]
After infection, cells were treated with compounds for 5 days, followed by luminescence measurement to assess bacterial viability. [1] Compound cytotoxicity was evaluated using a cell viability assay. [1] Checkerboard MIC assays were performed to evaluate drug combination effects, calculating fractional inhibitory concentrations (FICs). [1] |
| Animal Protocol |
In chronic TB models, mice were infected via aerosol or intranasal route with M. tuberculosis Erdman or H37Rv. [1]
Treatment began 3 weeks post-infection, administered orally 5 times per week for 4–8 weeks. [1] SPR719 (VXc-486) was dissolved in vitamin E TPGS for dosing, while pVXc-486 was dissolved in 0.5% carboxymethyl cellulose. [1] Lung bacterial burdens were assessed by plating homogenates on 7H10 agar. [1] In latent TB models, mice were immunized with BCG before M. tuberculosis challenge, followed by treatment for 1–2 months. [1] |
| ADME/Pharmacokinetics |
pVXc-486 is a phosphate prodrug that is rapidly converted to SPR719 (VXc-486) after oral administration, and the prodrug is undetectable in plasma after administration. [1]
The AUC of VXc-486 increases proportionally over a dose range of 3 to 100 mg/kg, while the Cmax increases proportionally within the same dose range. [1] Compared to the parent compound, pVXc-486 results in higher pulmonary exposure to VXc-486 after administration. [1] |
| References | |
| Additional Infomation |
SPR719 (VXc-486) is a DNA gyrase B inhibitor that is effective against fluoroquinolone-resistant strains because it targets a different DNA gyrase subunit (GyrB) than fluoroquinolone drugs (GyrA). [1] The resistance rate of VXc-486 is approximately 10⁻⁸, and identified resistance mutations include A92S and S208A in GyrB. [1] The compound exhibits slow bactericidal kinetics in vitro but is potent against dormant bacteria. [1] It is considered a promising candidate for the treatment of drug-resistant tuberculosis and nontuberculous mycobacterial infections. [1]
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| Molecular Formula |
C₂₁H₂₅FN₆O₃
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|---|---|
| Molecular Weight |
428.46
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| Exact Mass |
428.197
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| CAS # |
1384984-18-2
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| Related CAS # |
Fobrepodacin disodium;1384984-20-6
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| PubChem CID |
57524959
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| Appearance |
Yellow to brown solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.648
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| LogP |
1.42
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| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
632
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCNC(=O)NC1=NC2=C(N1)C=C(C(=C2[C@H]3CCCO3)F)C4=CN=C(N=C4)C(C)(C)O
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| InChi Key |
BKUISYCLLXCBJV-CQSZACIVSA-N
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| InChi Code |
InChI=1S/C21H25FN6O3/c1-4-23-20(29)28-19-26-13-8-12(11-9-24-18(25-10-11)21(2,3)30)16(22)15(17(13)27-19)14-6-5-7-31-14/h8-10,14,30H,4-7H2,1-3H3,(H3,23,26,27,28,29)/t14-/m1/s1
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| Chemical Name |
1-ethyl-3-[5-fluoro-6-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-4-[(2R)-oxolan-2-yl]-1H-benzimidazol-2-yl]urea
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| Synonyms |
SPR719 VXc486 SPR 719 VXc 486 SPR-719 VXc-486
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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 : ~20 mg/mL (~46.68 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3339 mL | 11.6697 mL | 23.3394 mL | |
| 5 mM | 0.4668 mL | 2.3339 mL | 4.6679 mL | |
| 10 mM | 0.2334 mL | 1.1670 mL | 2.3339 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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